OCTAHYDRO-CYCLOBUTA [1,2-c;3,4-c&#39;]DIPYRROL-2-YL

ABSTRACT

The invention provides novel compounds having the general formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , Y and R 2  are as described herein, compositions including the compounds and methods of using the compounds.

The present invention relates to organic compounds useful for therapy orprophylaxis in a mammal, and in particular to autotaxin (ATX) inhibitorswhich are inhibitors of lysophosphatidic acid (LPA) production and thusmodulators of LPA levels and associated signaling, for the treatment orprophylaxis of renal conditions, liver conditions, inflammatoryconditions, conditions of the nervous system, conditions of therespiratory system, vascular and cardiovascular conditions, fibroticdiseases, cancer, ocular conditions, metabolic conditions, cholestaticand other forms of chronic pruritus and acute and chronic organtransplant rejection.

The present invention provides novel compounds of formula (I)

wherein

-   -   R¹ is substituted quinolinyl, substituted        1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl,        substituted 1,2,3,4-tetrahydroisoquinolinyl, substituted        9H-carbazolyl, substituted chromanyl, substituted indolyl,        substituted naphthyl, substituted oxazolyl, substituted phenyl,        substituted phenylalkyl, substituted phenylcycloalkyl,        substituted phenoxyalkyl, substituted phenylalkoxy, substituted        phenylalkenyl, substituted phenylalkynyl, substituted        pyridazinyl, substituted pyridazinylalkyl, substituted        pyridazinylalkenyl, substituted pyridazinylalkynyl, substituted        pyridinyl, substituted pyridinylalkyl, substituted        pyridinylalkenyl, substituted pyridinylalkynyl, substituted        pyridinonyl, substituted pyridinonylalkyl, substituted        pyridinonylalkenyl, substituted pyridinonylalkynyl, substituted        thiophenyl, substituted thiophenylalkyl, substituted        thiophenylalkenyl, substituted thiophenylalkynyl, substituted        tetralinyl or substituted tetralinonyl, wherein substituted        quinolinyl, substituted 1,2,3,4-tetrahydroquinolinyl,        substituted isoquinolinyl, substituted        1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazolyl,        substituted chromanyl, substituted indolyl, substituted        naphthyl, substituted oxazolyl, substituted phenyl, substituted        phenylalkyl, substituted phenylcycloalkyl, substituted        phenoxyalkyl, substituted phenylalkoxy, substituted        phenylalkenyl, substituted phenylalkynyl, substituted        pyridazinyl, substituted pyridazinylalkyl, substituted        pyridazinylalkenyl, substituted pyridazinylalkynyl, substituted        pyridinyl, substituted pyridinylalkyl, substituted        pyridinylalkenyl, substituted pyridinylalkynyl, substituted        pyridinonyl, substituted pyridinonylalkyl, substituted        pyridinonylalkenyl, substituted pyridinonylalkynyl, substituted        thiophenyl, substituted thiophenylalkyl, substituted        thiophenylalkenyl, substituted thiophenylalkynyl, substituted        tetralinyl and substituted tetralinonyl are substituted with R⁶,        R⁷ and R⁸;    -   Y is —C(O)— or —S(O)₂—;    -   R² is substituted pyridinyl, substituted phenyl or is selected        from the ring systems A, B and C, wherein substituted pyridinyl        and substituted phenyl are substituted with one substituted        aminosulfonyl, wherein substituted aminosulfonyl is substituted        on the nitrogen atom with one to two substituents independently        selected from H, alkyl, cycloalkyl, cycloalkylalkyl,        hydroxyalkyl and alkoxyalkyl;

-   -   R³, R⁴ and R⁵ are independently selected from H, alkyl, halogen,        haloalkyl and alkoxy;    -   R⁶, R⁷ and R⁸ are independently selected from H, halogen, cyano,        cyanoalkyl, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl,        cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy,        cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl,        haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl,        alkylsulfonyl, furanyl, tetrahydropyranyl, phenyl, substituted        phenyl, phenylalkoxy, substituted phenylalkoxy, pyridinyl,        substituted pyridinyl, pyrrolyl, substituted pyrrolyl,        pyrrolydinyl and substituted pyrrolydinyl, wherein substituted        phenyl, substituted phenylalkoxy, substituted pyridinyl,        substituted pyrrolyl and substituted pyrrolydinyl are        substituted with one to three halogen;    -   and pharmaceutically acceptable salts.

Autotaxin (ATX) is a secreted enzyme also called ectonucleotidepyrophosphatase/phosphodiesterase 2 or lysophospholipase D, which isimportant for converting lysophosphatidyl choline (LPC) to the bioactivesignaling molecule lysophosphatidic acid (LPA). It has been shown thatplasma LPA levels are well correlated with ATX activity and hence ATX isbelieved to be an important source of extracellular LPA. Earlyexperiments with a prototype ATX inhibitor have shown that such acompound is able to inhibit the LPA synthesizing activity in mouseplasma. Work conducted in the 1970s and early 1980s has demonstratedthat LPA can elicit a wide range of cellular responses; including smoothmuscle cell contraction, platelet activation, cell proliferation,chemotaxis and others. LPA mediates its effects via signaling to severalG protein coupled receptors (GPCRs); the first members were originallydenoted Edg (endothelial cell differentiation gene) receptors orventricular zone gene-1 (vzg-1) but are now called LPA receptors. Theprototypic group now consists of LPA1/Edg-2/VZG-1, LPA2/Edg-4, andLPA3/Edg-7. Recently, three additional LPA receptors LPA4/p2y9/GPR23,LPA5/GPR92 and LPA6/p2Y5 have been described that are more closelyrelated to nucleotide-selective purinergic receptors than to theprototypic LPA1-3 receptors. The ATX-LPA signaling axis is involved in alarge range of physiological and pathophysiological functions,including, for example, nervous system function, vascular development,cardiovascular physiology, reproduction, immune system function, chronicinflammation, tumor metastasis and progression, organ fibrosis as wellas obesity and/or other metabolic diseases such as diabetes mellitus.Therefore, increased activity of ATX and/or increased levels of LPA,altered LPA receptor expression and altered responses to LPA maycontribute to the initiation, progression and/or outcome of a number ofdifferent pathophysiological conditions related to the ATX/LPA axis.

In accordance with the invention, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of diseases, disorders or conditions that areassociated with the activity of autotaxin and/or the biological activityof lysophosphatidic acid (LPA).

The compounds of formula (I) or their pharmaceutically acceptable saltsand esters herein inhibit autotaxin activity and therefore inhibit LPAproduction and modulate LPA levels and associated signaling. Autotaxininhibitors described herein are useful as agents for the treatment orprevention of diseases or conditions in which ATX activity and/or LPAsignaling participates, is involved in the etiology or pathology of thedisease, or is otherwise associated with at least one symptom of thedisease. The ATX-LPA axis has been implicated for example inangiogenesis, chronic inflammation, autoimmune diseases, fibroticdiseases, cancer and tumor metastasis and progression, ocularconditions, metabolic conditions such as obesity and/or diabetesmellitus, conditions such as cholestatic or other forms of chronicpruritus as well as acute and chronic organ transplant rejection.

Objects of the present invention are the compounds of formula (I) andtheir aforementioned salts and esters and their use as therapeuticallyactive substances, a process for the manufacture of the said compounds,intermediates, pharmaceutical compositions, medicaments containing thesaid compounds, their pharmaceutically acceptable salts or esters, theuse of the said compounds, salts or esters for the treatment orprophylaxis of disorders or conditions that are associated with theactivity of ATX and/or the biological activity of lysophosphatidic acid(LPA), particularly in the treatment or prophylaxis of renal conditions,liver conditions, inflammatory conditions, conditions of the nervoussystem, conditions of the respiratory system, vascular andcardiovascular conditions, fibrotic diseases, cancer, ocular conditions,metabolic conditions, cholestatic and other forms of chronic pruritusand acute and-chronic organ transplant rejection, and the use of thesaid compounds, salts or esters for the production of medicaments forthe treatment or prophylaxis of renal conditions, liver conditions,inflammatory conditions, conditions of the nervous system, conditions ofthe respiratory system, vascular and cardiovascular conditions, fibroticdiseases, cancer, ocular conditions, metabolic conditions, cholestaticand other forms of chronic pruritus and acute and chronic organtransplant rejection.

The term “alkenyl” denotes a monovalent linear or branched hydrocarbongroup of 2 to 7 carbon atoms with at least one double bond. Inparticular embodiments, alkenyl has 2 to 4 carbon atoms with at leastone double bond. Examples of alkenyl include ethenyl, propenyl,prop-2-enyl, isopropenyl, n-butenyl and iso-butenyl. Particular alkenylgroup is ethenyl.

The term “alkoxy” denotes a group of the formula —O—R′, wherein R′ is analkyl group. Examples of alkoxy group include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particularalkoxy group include methoxy, ethoxy and isopropoxy. More particularalkoxy group is isopropoxy.

The term “alkoxyalkoxy” denotes an alkoxy group wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by anotheralkoxy group. Examples of alkoxyalkoxy group include methoxymethoxy,ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy andethoxypropoxy. Particular alkoxyalkoxy group is methoxyethoxy.

The term “alkoxyalkoxyalkyl” denotes an alkyl group wherein at least oneof the hydrogen atoms of the alkyl group has been replaced by analkoxyalkoxy group. Examples of alkoxyalkoxyalkyl group includemethoxymethoxymethyl, ethoxymethoxymethyl, methoxyethoxymethyl,ethoxyethoxymethyl, methoxypropoxymethyl, ethoxypropoxymethyl,methoxymethoxyethyl, ethoxymethoxyethyl, methoxyethoxyethyl,ethoxyethoxyethyl, methoxypropoxyethyl and ethoxypropoxyethyl.

The term “alkoxyalkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced by an alkoxygroup. Exemplary alkoxyalkyl groups include methoxymethyl, ethoxymethyl,methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl andisopropoxymethyl. Particular alkoxyalkyl group is methoxpropyl.

The term “alkoxyhaloalkyl” denotes a haloalkyl group wherein at leastone of the hydrogen atoms of the haloalkyl group has been replaced by analkoxy group. Exemplary alkoxyalkyl groups includemethoxytrifluoroethyl, ethoxytrifluoroethyl, methoxytrifluoropropyl andethoxytrifluoropropyl.

The term “alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 12 carbon atoms. In particular embodiments,alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4carbon atoms. Examples of alkyl include methyl, ethyl, propyl,isopropyl, n-butyl, iso-butyl and sec-butyl, pentyl. Particular alkylgroups include methyl, isopropyl and iso-butyl.

The term “alkylsulfonyl” denotes a group of the formula —S(O)₂—R′,wherein R′ is an alkyl group. Examples of alkylsulfonyl groups includegroups of the formula —S(O)₂—R′, wherein R′ is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl or tert-butyl. Particular alkylsulfonylgroups include group of the formula —S(O)₂—R′, wherein R′ is methyl.

The term “amino” denotes a —NH₂ group.

The term “aminosulfonyl” denotes a —S(O)₂—NH₂ group.

The term “cyano” denotes a —C≡N group.

The term “cyanoalkyl” denotes an alkyl group wherein one of the hydrogenatoms of the alkyl group has been replaced by a cyano group. Exemplarycyanoalkyl groups include cyanomethyl, cyanoethyl and cyanopropyl.Particular alkoxyalkyl group is cyanomethyl.

The term “cycloalkoxy” denotes a group of the formula —O—R′, wherein R′is a cycloalkyl group. Examples of cycloalkoxy group includecyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxyand cyclooctyloxy. Particular cycloalkoxy group is cyclopropoxy.

The term “cycloalkoxyalkyl” denotes an alkyl group wherein at least oneof the hydrogen atoms of the alkyl group has been replaced by acycloalkoxy group. Examples of cycloalkoxyalkyl groups includecyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl,cyclobutoxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl,cyclohexyloxymethyl, cyclohexyloxyethyl, cycloheptyloxymethyl,cycloheptyloxyethyl, cyclooctyloxymethyl and cyclooctyloxyethyl.

The term “cycloalkyl” denotes a monovalent saturated monocyclic orbicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In particularembodiments, cycloalkyl denotes a monovalent saturated monocyclichydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means a ringsystem consisting of two saturated carbocycles having two carbon atomsin common. Examples for monocyclic cycloalkyl are cyclopropyl,cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples forbicyclic cycloalkyl are bicyclo[2.2.1]heptanyl or bicyclo[2.2.2]octanyl.Particular monocyclic cycloalkyl groups are cyclopropyl, cyclobutanyl,cyclopentyl and cyclohexyl. More particular monocyclic cycloalkyl groupis cyclopropyl.

The term “cycloalkylalkoxy” denotes an alkoxy group wherein at least oneof the hydrogen atoms of the alkoxy group is replaced by a cycloalkylgroup. Examples of cycloalkylalkoxy include cyclopropylmethoxy,cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy,cycloheptylmethoxy and cyclooctylmethoxy. Particular cycloalkylalkoxygroup is cyclopropylmethoxy.

The term “cycloalkylalkoxyalkyl” denotes an alkyl group wherein at leastone of the hydrogen atoms of the alkyl group is replaced by acycloalkylalkoxy group. Examples of cycloalkylalkoxyalkyl includecyclopropylmethoxymethyl, cyclopropylmethoxyethyl,cyclobutylmethoxymethyl, cyclobutylmethoxyethyl,cyclopentylmethoxyethyl, cyclopentylmethoxyethyl,cyclohexylmethoxymethyl, cyclohexylmethoxyethyl,cycloheptylmethoxymethyl, cycloheptylmethoxyethyl,cyclooctylmethoxymethyl and cyclooctylmethoxyethyl.

The term “cycloalkylalkyl” denotes an alkyl group wherein at least oneof the hydrogen atoms of the alkyl group is replaced by a cycloalkylgroup. Examples of cycloalkylalkyl include cyclopropylmethyl,cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl,2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl,bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl,bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl,adamentanylmethyl and adamantanylethyl. Particular examples ofcycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl,bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl,bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl,adamentanylmethyl and adamantanylethyl. Further particular examplescycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl,bicyclo[4.1.0]heptanylmethyl, bicyclo[2.2.2]octanylmethyl,adamentanylmethyl and adamantanylethyl.

The term “haloalkoxy” denotes an alkoxy group wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by the same ordifferent halogen atoms. The term “perhaloalkoxy” denotes an alkoxygroup where all hydrogen atoms of the alkoxy group have been replaced bythe same or different halogen atoms. Examples of haloalkoxy includefluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy,trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy.Particular haloalkoxy group are trifluoromethoxy and trifluoroethoxy.

The term “haloalkyl” denotes an alkyl group wherein at least one of thehydrogen atoms of the alkyl group has been replaced by the same ordifferent halogen atoms. The term “perhaloalkyl” denotes an alkyl groupwhere all hydrogen atoms of the alkyl group have been replaced by thesame or different halogen atoms. Examples of haloalkyl includefluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl,trifluoromethylethyl and pentafluoroethyl. Particular haloalkyl groupsare trifluoromethyl and trifluoroethyl.

The term “halogen” and “halo” are used interchangeably herein and denotefluoro, chloro, bromo, or iodo. Particular halogens are chloro andfluoro. More particular halogen is chloro.

The term “hydroxy” denotes a —OH group.

The term “hydroxyalkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced by a hydroxygroup. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl,hydroxy-1-methyl-ethyl, hydroxypropyl, hydroxymethylpropyl anddihydroxypropyl. Particular examples are hydroxymethyl and hydroxyethyl.

The term “hydroxyhaloalkyl” denotes a haloalkyl group wherein at leastone of the hydrogen atoms of the haloalkyl group has been replaced by anhydroxy group. Exemplary hydroxyhaloalkyl groups includehydroxytrifluoroethyl and hydroxytrifluoropropyl. Particularhydroxyhaloalkyl groups include hydroxytrifluoroethyl.

The term “phenoxy” denotes a group of the formula —O—R′, wherein R′ is aphenyl.

The term “phenoxyalkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced by a phenoxygroup. Exemplary phenoxyalkyl groups include phenoxymethyl, phenoxyethyland phenoxypropyl. Particular alkoxyalkyl group is phenoxymethyl.

The term “phenylalkenyl” denotes an alkenyl group wherein at least oneof the hydrogen atoms of the alkenyl group has been replaced a phenyl.Particular phenylalkenyl group is phenylethenyl.

The term “phenylalkoxy” denotes an alkoxy group wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by a phenylgroup. Examples of phenylalkoxy include phenylmethoxy and phenylethoxy.Particular phenylalkoxy group is phenylmethoxy.

The term “phenylalkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced a phenyl.Particular phenylalkyl groups are benzyl, phenethyl and phenylpropyl.More particular phenylalkyl groups are benzyl and phenethyl. Furtherparticular phenylalkyl group is benzyl.

The term “phenylalkynyl” denotes an alkynyl group wherein at least oneof the hydrogen atoms of the alkynyl group has been replaced a phenyl.Particular phenylalkynyl group is phenylethynyl.

The term “phenylcyloalkyl” denotes a cycloalkyl group wherein at leastone of the hydrogen atoms of the cycloalkyl group has been replaced aphenyl. Particular phenylcycloalkyl group is phenylcyclopropyl.

The term “pyridazinylalkenyl” denotes an alkenyl group wherein at leastone of the hydrogen atoms of the alkenyl group has been replaced apyridazinyl. Particular pyridazinylalkenyl group is pyridazinylethenyl.

The term “pyridazinylalkyl” denotes an alkyl group wherein at least oneof the hydrogen atoms of the alkyl group has been replaced apyridazinyl. Particular pyridazinylalkyl groups are pyridazinylmethyl,pyridazinylethyl and pyridazinylpropyl. More particular pyridazinylalkylgroup is pyridazinylethyl.

The term “pyridazinylalkynyl” denotes an alkynyl group wherein at leastone of the hydrogen atoms of the alkynyl group has been replaced apyridazinyl. Particular pyridazinylalkynyl group is pyridazinylethynyl.

The term “pyridinonylalkenyl” denotes an alkenyl group wherein at leastone of the hydrogen atoms of the alkenyl group has been replaced apyridinonyl. Particular pyridinonylalkenyl group is pyridinonylethenyl.

The term “pyridinonylalkyl” denotes an alkyl group wherein at least oneof the hydrogen atoms of the alkyl group has been replaced apyridinonyl. Particular pyridinonylalkyl groups are pyridinonylmethyl,pyridinonylethyl and pyridinonylpropyl. More particular pyridinonylalkylgroup is pyridinonylethyl.

The term “pyridinonyl alkynyl” denotes an alkynyl group wherein at leastone of the hydrogen atoms of the alkynyl group has been replaced apyridinonyl. Particular pyridinonyl alkynyl group is pyridinonylethynyl.

The term “pyridinylalkenyl” denotes an alkenyl group wherein at leastone of the hydrogen atoms of the alkenyl group has been replaced apyridinyl. Particular pyridinylalkenyl group is pyridinylethenyl.

The term “pyridinylalkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced a pyridinyl.Particular pyridinylalkyl groups are pyridinylmethyl, pyridinylethyl andpyridinylpropyl. More particular pyridinylalkyl group is pyridinylethyl.

The term “pyridinylalkynyl” denotes an alkynyl group wherein at leastone of the hydrogen atoms of the alkynyl group has been replaced apyridinyl. Particular pyridinylalkynyl group is pyridinylethynyl.

The term “thiophenylalkenyl” denotes an alkenyl group wherein at leastone of the hydrogen atoms of the alkenyl group has been replaced athiophenyl. Particular thiophenylalkenyl group is thiophenylethenyl.

The term “thiophenylalkyl” denotes an alkyl group wherein at least oneof the hydrogen atoms of the alkyl group has been replaced a thiophenyl.Particular thiophenylalkyl groups are thiophenylmethyl, thiophenylethyland thiophenylpropyl. More particular thiophenylalkyl group isthiophenylmethyl.

The term “thiophenylalkynyl” denotes an alkynyl group wherein at leastone of the hydrogen atoms of the alkynyl group has been replaced athiophenyl. Particular thiophenylalkynyl group is thiophenylethynyl.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, in particular hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition, these salts may be preparedby addition of an inorganic base or an organic base to the free acid.Salts derived from an inorganic base include, but are not limited to,the sodium, potassium, lithium, ammonium, calcium, magnesium salts andthe like. Salts derived from organic bases include, but are not limitedto salts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.Particular pharmaceutically acceptable salts of compounds of formula (I)are the sodium and potassium salts.

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention.

The term “protecting group” (PG) denotes a group which selectivelyblocks a reactive site in a multifunctional compound such that achemical reaction can be carried out selectively at another unprotectedreactive site in the meaning conventionally associated with it insynthetic chemistry. Protecting groups can be removed at the appropriatepoint. Exemplary protecting groups are amino-protecting groups,carboxy-protecting groups or hydroxy-protecting groups. Particularprotecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl(Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. Furtherparticular protecting groups are the tert-butoxycarbonyl (Boc) and thefluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting groupis the tert-butoxycarbonyl (Boc) group.

The abbreviation uM means microMolar and is equivalent to the symbol M.

The abbreviation uL means microliter and is equivalent to the symbol μL.

The abbreviation ug means microgram and is equivalent to the symbol μg.

The compounds of formula (I) can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention the asymmetric carbonatom can be of the “R” or “S” configuration.

Also an embodiment of the present invention are compounds according toformula (I) as described herein and pharmaceutically acceptable salts oresters thereof, in particular compounds according to formula (I) asdescribed herein and pharmaceutically acceptable salts thereof, moreparticularly compounds according to formula (I) as described herein.

A more particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein the compounds areof formula (Ic).

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R¹ is substituted quinolinyl,substituted 1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl,substituted 1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazolyl,substituted chromanyl, substituted indolyl, substituted naphthyl,substituted oxazolyl, substituted phenyl, substituted phenylalkyl,substituted phenoxyalkyl, substituted phenylalkoxy, substitutedphenylalkenyl, substituted pyridazinyl, substituted pyridinyl,substituted pyridinonyl, substituted tetralinyl or substitutedtetralinonyl, wherein substituted quinolinyl, substituted1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl, substituted1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazolyl, substitutedchromanyl, substituted indolyl, substituted naphthyl, substitutedoxazolyl, substituted phenyl, substituted phenylalkyl, substitutedphenoxyalkyl, substituted phenylalkoxy, substituted phenylalkenyl,substituted pyridazinyl, substituted pyridinyl, substituted pyridinonyl,substituted tetralinyl and substituted tetralinonyl are substituted withR⁶, R⁷ and R⁸.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹ is substitutedquinolinyl, substituted indolyl, substituted naphthyl, substitutedphenylalkoxy, substituted phenylalkenyl or substituted pyridinyl,wherein substituted quinolinyl, substituted indolyl, substitutednaphthyl, substituted phenylalkoxy, substituted phenylalkenyl andsubstituted pyridinyl are substituted with R⁶, R⁷ and R⁸.

In a further embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹ is substitutedquinolinyl, substituted indolyl, substituted naphthyl or substitutedpyridinyl, wherein substituted quinolinyl, substituted indolyl,substituted naphthyl and substituted pyridinyl are substituted with R⁶,R⁷ and R⁸. The present invention also relates to compounds according toformula (I) as described herein, wherein R² is selected from the ringsystems A and C.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R² is the ringsystem A and of formula (Ia).

Also an embodiment of the present invention are compounds according toformula (I) as described herein, wherein Y is —C(O)—.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R³, R⁴ and R⁵ are independentlyselected from H and halogen.

A further embodiment of the present invention are compounds according toformula (I) as described herein, wherein R³, R⁴ and R⁵ are H.

The present invention also relates to compounds according to formula (I)as described herein, wherein R⁶ is H, halogen, cyano, cyanoalkyl, alkyl,haloalkyl, cycloalkylalkoxy, alkoxy, alkoxyalkyl, haloalkoxy,alkoxyalkoxy, phenyl, phenylalkoxy or phenyl substituted with one tothree halogen.

A further embodiment of the present invention are compounds according toformula (I) as described herein, wherein R⁶ is alkoxy, haloalkoxy oralkoxyalkoxy.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R⁷ is H, halogen, alkyl,cycloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, furanyl ortetrahydropyranyl.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R⁷ is H orhalogen.

Also an embodiment of the present invention are compounds according toformula (I) as described herein, wherein R⁸ is H or alkyl.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R⁸ is H.

A more particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹ is substitutedquinolinyl, substituted indolyl, substituted naphthyl or substitutedpyridinyl, wherein substituted quinolinyl, substituted indolyl,substituted naphthyl and substituted pyridinyl are substituted with R⁶,R⁷ and R⁸, Y is —C(O)— and R² is the ring system A and of formula (Ib).

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein the compounds areof formula (Ic).

Particular examples of compounds of formula (I) as described herein areselected from

-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-naphthalen-2-yl)-methanone;-   1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propan-1-one;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4′-fluoro-biphenyl-4-yl)-methanone;-   (E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-bromo-naphthalen-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-methoxy-naphthalen-2-yl)-methanone;-   (E)-1-[(3aS,3bS,6aR,6bR)-5-((R)-4,    5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone;-   6-[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-naphthalene-2-carbonitrile;-   1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-2-(4-trifluoromethoxy-phenoxy)-ethanone;-   1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-2-(2-isopropyl-phenoxy)-ethanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(5-trifluoromethoxy-1H-indol-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-trifluoromethoxy-1H-indol-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-naphthalen-2-yl-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-methyl-naphthalen-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(7-methyl-naphthalen-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-phenyl-naphthalen-2-yl)-methanone;-   (6-bromo-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,    5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4′-chloro-biphenyl-4-yl)-methanone;-   (4′-chloro-biphenyl-4-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(5-trifluoromethoxy-1H-indol-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-trifluoromethoxy-1H-indol-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(3-methoxy-naphthalen-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-methoxy-naphthalen-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-indol-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-methyl-1H-indol-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-cyclopropylmethoxy-naphthalen-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-methoxy-naphthalen-2-yl)-methanone;-   2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-1H-indole-5-carbonitrile;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(3-methoxy-phenyl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-methoxy-quinolin-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-methanone;-   [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1,2,3,4-tetrahydro-naphthalen-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-methyl-5-trifluoromethoxy-1H-indol-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-1H-indol-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-1-methyl-1H-indol-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-methyl-1H-indol-2-yl)-methanone;-   {2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-indol-1-yl}-acetonitrile;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-isobutyl-1H-indol-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-quinolin-2-yl-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-isoquinolin-3-yl-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-indol-6-yl)-methanone;-   3-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-3,4-dihydro-2H-naphthalen-1-one;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-chroman-2-yl-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-indol-5-yl)-methanone;-   (4-methoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,    5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[6-(4-chloro-phenyl)-pyridin-3-yl]-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-methoxy-isoquinolin-3-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-methyl-quinolin-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(5-chloro-1H-indol-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-naphthalen-2-yl]-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(7-phenyl-naphthalen-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-ethoxy-naphthalen-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-naphthalen-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-benzyloxy-1H-indol-6-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone;-   [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-methanone;-   [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[1-(2-methoxy-ethoxy)-isoquinolin-3-yl]-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-cyclopropylmethoxy-isoquinolin-3-yl)-methanone;-   (4-isopropoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,    5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[1-(2,2,2-trifluoro-ethoxy)-isoquinolin-3-yl]-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-1H-indol-6-yl)-methanone;-   4-[(3aS,3bS,6aR,6bR)-5-(4-isopropoxy-naphthalene-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-benzenesulfonamide;-   [6-(4-chloro-phenyl)-pyridin-3-yl]-[(3aR,3bS,6aR,6bS)-5-((R)-4,    5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   (1-cyclopropylmethoxy-isoquinolin-3-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,    5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-1-methyl-1H-indol-6-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-ethoxy-quinolin-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-quinolin-2-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-9H-carbazol-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-quinolin-2-yl]-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-7-trifluoromethyl-quinolin-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-cyclopropylmethoxy-quinolin-2-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[5-(4-chloro-phenyl)-pyridin-2-yl]-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-ethoxy-isoquinolin-3-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-ethyl-4-isopropoxy-1H-indol-6-yl)-methanone;-   6-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-3-(4-chloro-phenyl)-1H-pyridin-2-one;-   1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(7-chloro-4-ethoxy-quinolin-2-yl)-methanone;-   (7-chloro-4-ethoxy-quinolin-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,    5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-5,6,7,    8-tetrahydro-naphthalen-2-yl)-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(2-methoxy-ethoxy)-7-trifluoromethyl-quinoline-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-6-trifluoromethyl-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-ethoxy-1-ethyl-1H-indol-5-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[1-ethyl-4-(2,2,2-trifluoro-ethoxy)-1H-indol-5-yl]-methanone;-   5-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-pyridine-2-sulfonic    acid amide;-   (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(2,2,2-trifluoro-ethoxy)-quinoline-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[4-ethoxy-1-(2,2,2-trifluoro-ethyl)-1H-indole-6-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-chloro-4-cyclopropylmethoxy-pyridine-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   (3,4-dimethyl-phenyl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-5,6,7,8-tetrahydro-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   (1H-benzotriazol-5-yl)-[(3aS,3bS,6aR,6bR)-5-(4′-chloro-biphenyl-3-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-7-methoxy-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   [(3aS,3bS,6aR,6bR)-5-(4-Ethoxy-6-trifluoromethyl-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-methanone;-   [(3aS,3bS,6aR,6bR)-5-(1-ethoxy-isoquinoline-3-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-methanone;-   (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-octahydro-cyclobuta[1,2-c;    3,4-c′]dipyrrol-2-yl]-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[5-cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-cyclopropyl-5-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone′]dipyrrol-2-yl}-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-4-ethoxy-quinolin-2-yl)-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   [(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-pyridazine-3-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(3,4-dimethyl-phenyl)-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-2-methyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-5-trifluoromethyl-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-(tetrahydro-pyran-4-yl)-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(4-chloro-phenyl)-5-(2,    2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-furan-2-yl-6-(2,2,2-tri    fluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-chloro-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   [(3aS,3bR,6aS,6bR)-5-(4-ethoxy-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-fluoro-1H-benzotriazol-5-yl)-methanone;-   {(3aS,3bS,6aR,6bR)-5-[5-methanesulfonyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-phenyl-methanone;-   (3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylicacid    4-trifluoromethoxy-benzyl ester;-   (3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylic    acid 3,5-dichloro-benzyl ester;-   (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4′-fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-chloro-naphthalene-2-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone;

and pharmaceutically acceptable salts thereof.

Further particular examples of compounds of formula (I) as describedherein are selected from

-   (E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone;-   (4-isopropoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,    5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;-   4-[(3aS,3bS,6aR,6bR)-5-(4-isopropoxy-naphthalene-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-benzenesulfonamide;-   [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-1-methyl-1H-indol-6-yl)-methanone;-   [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-quinolin-2-yl]-methanone;-   (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;-   (3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylicacid    4-trifluoromethoxy-benzyl ester;

and pharmaceutically acceptable salts thereof.

Processes for the manufacture of compounds of formula (I) as describedherein are an object of the invention.

The preparation of compounds of formula (I) of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following general schemes. The skillsrequired for carrying out the reactions and purifications of theresulting products are known to those persons skilled in the art. Incase a mixture of enantiomers or diastereoisomers is produced during areaction, these enantiomers or diastereoisomers can be separated bymethods described herein or known to the man skilled in the art such ase.g. (chiral) chromatography or crystallization. The substituents andindices used in the following description of the processes have thesignificance given herein.

Compounds of general formula (I) can be synthesised from amine precursor1 and appropriate reagents, using methods well known in the art.

For instance, amine 1 is reacted with a suitable chloroformate ester offormula R¹—O—C(O)—Cl (2) (R¹=substituted phenylalkyl), or with animidazole-1-carboxylate ester of formula (3A, R¹=substitutedphenylalkyl), or with a succinimidyl carbonate derivative of formula(3B, R¹=phenylalkyl), leading to a compound of formula (I) wherein R¹ issubstituted phenylalkoxy.

The reaction is performed in a suitable solvent such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, ormixtures thereof, in the presence or not of a base, e. g.,triethylamine, diisopropylethylamine, pyridine, potassiumhydrogencarbonate, potassium carbonate, at temperatures between 0° C.and the boiling point of the solvent or solvent mixture.

Chloroformate esters 2 are commercially available or can be synthesisedfrom the corresponding alcohol of formula R¹—OH (R¹=substitutedphenylalkyl), by reaction with phosgene or a phosgene equivalent (e. g.,diphosgene, triphosgene), as described in the literature.

Imidazole-1-carboxylate esters 3A are synthesised from the correspondingalcohols of formula R¹—OH (R¹=substituted phenylalkyl), by reaction with1,1′-carbonyldiimidazole. The reaction is performed at room temperature,in a solvent such as dichloromethane, tetrahydrofuran or acetonitrile.The imidazole-1-carboxylate esters 3A are typically not isolated butdirectly reacted with amines 1 as described above.

Succinimidyl carbonate derivatives 3B are synthesised from thecorresponding alcohols of formula R¹—OH (R¹=substituted phenylalkyl), byreaction with N,N′-disuccinimidyl carbonate. The reaction is performedat room temperature, in a solvent such as dichloromethane,tetrahydrofuran, or acetonitrile, optionally in the presence of a base,e. g., triethylamine. The succinimidyl carbonate derivatives 3B aretypically not isolated but directly reacted with amines 1 as describedabove.

Alcohols of formula R¹—OH are commercially available or can be producedby methods described herein or known in the art.

Alternatively, amine 1 is reacted with a suitableN-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinoline 4, leading tocompounds of formula (I) wherein R¹ is substituted1,2,3,4-tetrahydroisoquinolin-2-yl.

N-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinolines (4) are synthesisedfrom the corresponding 1,2,3,4-tetrahydroisoquinolines 5 by reactionwith phosgene or a phosgene equivalent, as described herein or in theliterature.

Alternatively, amine 1 is reacted with a suitable carboxylic acid offormula R¹—COOH (6) leading to a compound of formula (I). The reactionis performed in the presence of a coupling agent such as1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate or bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate, in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between −40° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine and/or4-(dimethylamino)pyridine.

Amine 1 can also be reacted with suitable acylating reagents such asacyl chlorides of formula R¹—COCl (7) to lead to compounds of formula(I). The reaction is performed in a solvent such as dichloromethane,tetrahydrofuran, or N,N-dimethylformamide, in the presence of a basesuch as triethylamine or 4-methylmorpholine, at temperatures between 0°C. and 80° C.

Carboxylic acids (6) and acyl halides (7) are commercially available orcan be prepared as described herein or in the literature.

Alternatively, amine 1 is reacted with a suitable sulfonyl chloride offormula R¹—SO₂Cl (8), leading to compounds of formula (I) wherein Y is—S(O₂)—. The reaction is performed in a suitable solvent such asdichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile,acetone, water, or mixtures thereof, in the presence of a base, e. g.,triethylamine, diisopropylethylamine, pyridine, potassiumhydrogencarbonate, potassium carbonate, at temperatures between 0° C.and the boiling point of the solvent or solvent mixture.

Sulfonyl chlorides (8) are commercially available or can be synthesisedas described herein or in the literature.

Amines of general formula 1 are synthesised from tert-butyl carbamateprecursors 9.

The deprotection of 9 may be performed in the presence of a suitableacid, e. g, hydrochloric acid or trifluoroacetic acid, in a solvent suchas water, 2-propanol, dichloromethane, or 1,4-dioxane at temperaturesbetween 0° C. and 30° C., leading to amine 1.

Amides 9 can be produced from amine 10 by reaction with appropriatereagents, using methods known in the art.

For instance, amine 10 is reacted with a suitable carboxylic acid offormula R²—COOH (11), leading to compounds of formula 9, The reaction isperformed in the presence of a coupling agent such as1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate or bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate, in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between −40° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine and/or4-(dimethylamino)pyridine.

Boc-protected amine 10 can be produced from diamine 12 using a suitablereagent, e. g., di-tert-butyl dicarbonate. The reaction is performed ina suitable solvent, e. g., dichloromethane, chloroform, ortetrahydrofuran, at temperatures between 0° C. and 30° C.

Alternatively, 10 can be produced from 12 in a two step sequence. In thefirst step, 12 is reacted with excess di-tert-butyl dicarbonate, leadingto the diprotected intermediate 13. The dicarbamate 13 ismono-deprotected under suitable conditions, e. g., with hydrogenchloride, in solvents such as ethyl acetate, diethyl ether, 2-propanol,or mixtures thereof, leading to 10 as the hydrochloride salt.

Amines of general formula 1 can also be synthesised from diamine 12 byreaction with appropriate reagents, using methods known in the art. Forinstance, diamine 12 is reacted with a suitable carboxylic acid offormula R²—COOH (11), leading to compounds of formula 1, The reaction isperformed in the presence of a coupling agent such as1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate or bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate, in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between −40° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine.

Compounds of formula (I), can also be produced from amine precursors ofgeneral formula 14 by reaction with appropriate reagents, using methodsknown in the art.

For instance, amine 14 is reacted with a suitable carboxylic acid offormula R²—COOH (11), leading to compounds of formula (I). The reactionis performed in the presence of a coupling agent such as1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate or bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate, in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between −40° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine and/or4-(dimethylamino)pyridine.

Amines 14 can be synthesised from diamine 12, using methods and reagentsknown in the art.

For instance, diamine 12 is reacted with a suitable chloroformate esterof formula R¹—O—C(O)—Cl (2) (R¹=substituted phenylalkyl), or with animidazole-1-carboxylate ester of formula (3A, R¹=substitutedphenylalkyl), or with a succinimidyl carbonate derivative of formula(3B, R¹=phenylalkyl), leading to a compound of formula 14 wherein R¹ issubstituted phenylalkoxy. The reaction is performed in a suitablesolvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide,acetonitrile, acetone, water, or mixtures thereof, in the presence ornot of a base, e. g., triethylamine, diisopropylethylamine, pyridine,potassium hydrogencarbonate, potassium carbonate, at temperaturesbetween 0° C. and the boiling point of the solvent or solvent mixture.

Alternatively, diamine 12 is reacted with a suitableN-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinoline 4, leading tocompounds of formula 14 wherein R¹ is substituted1,2,3,4-tetrahydroisoquinolin-2-yl.

Alternatively, diamine 12 is reacted with a suitable carboxylic acid offormula R¹—COOH (6) leading to a compound of formula 14. The reaction isperformed in the presence of a coupling agent such as1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate or bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate, in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between −40° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine and/or4-(dimethylamino)pyridine.

Diamine 12 can also be reacted with suitable acylating reagents such asacyl chlorides of formula R¹—COCl (7) to lead to compounds of formula14. The reaction is performed in a solvent such as dichloromethane,tetrahydrofuran, or N,N-dimethylformamide, in the presence of a basesuch as triethylamine or 4-methylmorpholine, at temperatures between 0°C. and 80° C.

Alternatively, diamine 12 is reacted with a suitable sulfonyl chlorideof formula R¹—SO₂C (8), leading to compounds of formula 14 wherein Y is—S(O₂)—. The reaction is performed in a suitable solvent such asdichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile,acetone, water, or mixtures thereof, in the presence of a base, e. g.,triethylamine, diisopropylethylamine, pyridine, potassiumhydrogencarbonate, potassium carbonate, at temperatures between 0° C.and the boiling point of the solvent or solvent mixture.

Alternatively, amines 14 can be synthesised from their tert-butylcarbamate derivatives of formula 15 by carbamate deprotection. Thedeprotection may be performed in the presence of a suitable acid, e. g,hydrochloric acid or trifluoroacetic acid, in a solvent such as water,2-propanol, dichloromethane, or 1,4-dioxane, at temperatures between 0°C. and 30° C.

Intermediates 15 can be produced from amine 10 by reaction withappropriate reagents, using methods known in the art.

For instance, amine 10 is reacted with a suitable chloroformate ester offormula R¹—O—C(O)—Cl (2) (R¹=substituted phenylalkyl), or with animidazole-1-carboxylate ester of formula (3A, R¹=substitutedphenylalkyl), or with a succinimidyl carbonate derivative of formula(3B, R¹=phenylalkyl), leading to a compound of formula 15 wherein R¹ issubstituted phenylalkoxy. The reaction is performed in a suitablesolvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide,acetonitrile, acetone, water, or mixtures thereof, in the presence ornot of a base, e. g., triethylamine, diisopropylethylamine, pyridine,potassium hydrogencarbonate, potassium carbonate, at temperaturesbetween 0° C. and the boiling point of the solvent or solvent mixture.

Alternatively, amine 10 is reacted with a suitableN-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinoline 4, leading tocompounds of formula 15 wherein R¹ is substituted1,2,3,4-tetrahydroisoquinolin-2-yl.

Alternatively, amine 10 is reacted with a suitable carboxylic acid offormula R¹—COOH (6) leading to a compound of formula 15. The reaction isperformed in the presence of a coupling agent such as1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate or bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate, in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between −40° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine and/or4-(dimethylamino)pyridine.

Amine 12 can also be reacted with suitable acylating reagents such asacyl chlorides of formula R¹—COCl (7) to lead to compounds of formula15. The reaction is performed in a solvent such as dichloromethane,tetrahydrofuran, or N,N-dimethylformamide, in the presence of a basesuch as triethylamine or 4-methylmorpholine, at temperatures between 0°C. and 80° C.

Alternatively, amine 10 is reacted with a suitable sulfonyl chloride offormula R¹—SO₂Cl (8), leading to compounds of formula 15 wherein Y is—S(O₂)—. The reaction is performed in a suitable solvent such asdichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile,acetone, water, or mixtures thereof, in the presence of a base, e. g.,triethylamine, diisopropylethylamine, pyridine, potassiumhydrogencarbonate, potassium carbonate, at temperatures between 0° C.and the boiling point of the solvent or solvent mixture.

Diamine 12 can be synthesised in three step from N-benzylmaleimide (16),as illustrated in scheme 1.

In step 1, scheme 1, N-benzylmaleimide (16) undergoes photodimerisationby irradiation with ultraviolet light (λ=300 nm), leading to diimide 17.This reaction is performed in a suitable solvent, e. g., acetonitrile ordichloromethane, at temperatures between −30° C. and +40° C. Thereaction can be performed either in batch mode or, more preferably, in acontinuous flow reactor. The dimeric products can be formed as a mixtureof stereoisomers (i. e., 3aS,3bS,6aR,6bR-17 and 3aS,3bR,6aS,6bR-17),which can be separated, e. g., by crystallisation.

In step 2, scheme 1, diimide 17 is reduced to the corresponding diamine18, using reagents and conditions known in the art. The reaction isperformed, e. g., using lithium aluminum hydride, in a solvent such asdiethyl ether or tetrahydrofuran, at temperatures between 0° C. and theboiling point of the solvent.

In step 3, scheme 1, the benzyl groups of 18 are removed, leading todiamine 12, using methods and reagents known in the art, e. g., bycatalytic hydrogenation. The reaction is performed in a suitablesolvent, e. g., methanol or ethanol, at hydrogen pressures between 1 barand 100 bar, at temperatures between 0° C. and 100° C., in the presenceof a suitable catalyst, e. g., palladium on activated charcoal.

Also an embodiment of the present invention is a process to prepare acompound of formula (I) as defined above comprising the reaction of acompound of formula (II) in the presence of a compound of formula (III);

wherein R¹, R², A and Y are as defined above.

In particular, in the presence of a coupling agent such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate, in a solvent such as N,N-dimethylformamide, in thepresence of a base such as 4-methylmorpholine and at a temperaturecomprised between −78° C. and reflux, particularly between −10° C. androom temperature.

Also an object of the present invention is a compound according toformula (I) as described herein for use as a therapeutically activesubstance.

Likewise an object of the present invention is a pharmaceuticalcomposition comprising a compound according to formula (I) as describedherein and a therapeutically inert carrier.

A more particular object of the invention is the use of a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of fibrotic diseases, cancer and ocular conditions.

A furthermore particular object of the invention is the use of acompound according to formula (I) as described herein for the treatmentor prophylaxis of fibrotic diseases and ocular conditions.

Renal conditions include, but are not limited to, acute kidney injuryand chronic renal disease with and without proteinuria includingend-stage renal disease (ESRD). In more detail, this includes decreasedcreatinine clearance and decreased glomerular filtration rate,micro-albuminuria, albuminuria and proteinuria, glomerulosclerosis withexpansion of reticulated mesangial matrix with or without significanthypercellularity (particularly diabetic nephropathy and amyloidosis),focal thrombosis of glomerular capillaries (particularly thromboticmicroangiopathies), global fibrinoid necrosis, ischemic lesions,malignant nephrosclerosis (such as ischemic retraction, reduced renalblood flow and renal arteriopathy), swelling and proliferation ofintracapillary (endothelial and mesangial) and/or extracapillary cells(crescents) like in glomerular nephritis entities, focal segmentalglomerular sclerosis, IgA nephropathy, vasculitides/systemic diseases aswell as acute and chronic kidney transplant rejection.

Liver conditions include, but are not limited to, liver cirrhosis,hepatic congestion, cholestatic liver disease including pruritus,nonalcoholic steatohepatitis and acute and chronic liver transplantrejection.

Inflammatory conditions include, but are not limited to, arthritis,osteoarthritis, multiple sclerosis, systemic lupus erythematodes,inflammatory bowel disease, abnormal evacuation disorder and the like aswell as inflammatory airways diseases such as idiopathic pulmonaryfibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronicasthma bronchiale.

Further conditions of the respiratory system include, but are notlimited to, other diffuse parenchymal lung diseases of differentetiologies including iatrogenic drug-induced fibrosis, occupationaland/or environmental induced fibrosis, systemic diseases andvasculitides, granulomatous diseases (sarcoidosis, hypersensitivitypneumonia), collagen vascular disease, alveolar proteinosis, Langerhanscell granulomatosis, lymphangioleiomyomatosis, inherited diseases(Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis,metabolic storage disorders, familial interstitial lung disease),radiation induced fibrosis, silicosis, asbestos induced pulmonaryfibrosis or acute respiratory distress syndrome (ARDS).

Conditions of the nervous system include, but are not limited to,neuropathic pain, schizophrenia, neuro-inflammation (e.g. astrogliosis),peripheral and/or autonomic (diabetic) neuropathies and the like.

Vascular conditions include, but are not limited to, atherosclerosis,thrombotic vascular disease as well as thrombotic microangiopathies,proliferative arteriopathy (such as swollen myointimal cells surroundedby mucinous extracellular matrix and nodular thickening),atherosclerosis, decreased vascular compliance (such as stiffness,reduced ventricular compliance and reduced vascular compliance),endothelial dysfunction and the like.

Cardiovascular conditions include, but are not limited to, acutecoronary syndrome, coronary heart disease, myocardial infarction,arterial and pulmonary hypertension, cardiac arrhythmia such as atrialfibrillation, stroke and other vascular damage.

Fibrotic diseases include, but are not limited to myocardial andvascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis,skin fibrosis, scleroderma and encapsulating peritonitis. A particularfibrotic disease is idiopathic pulmonary fibrosis.

In a particular embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of organ or skin fibrosis.

In another embodiment, the fibrotic disease is renal tubulo-interstitialfibrosis or glomerulosclerosis.

In another embodiment, the fibrotic disease is non-alcoholic liversteatosis, liver fibrosis or liver cirrhosis.

In another embodiment, the fibrotic disease is idiopathic pulmonaryfibrosis.

Cancer and cancer metastasis include, but are not limited to, breastcancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma,glioma, hepatic carcinoma, gastrointestinal cancers and progression andmetastatic aggressiveness thereof.

Ocular conditions include, but are not limited to, proliferative andnon-proliferative (diabetic) retinopathy, dry and wet age-relatedmacular degeneration (AMD), (diabetic) macular edema, centralarterial/venous occlusion, traumatic injury, glaucoma and the like. Aparticular ocular condition is glaucoma.

Metabolic conditions include, but are not limited to, obesity anddiabetes.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of cholestatic or non-cholestatic chronicpruritus.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofrenal conditions, liver conditions, inflammatory conditions, conditionsof the nervous system, conditions of the respiratory system, vascularand cardiovascular conditions, fibrotic diseases, cancer, ocularconditions, metabolic conditions, cholestatic and other forms of chronicpruritus and acute and chronic organ transplant rejection.

The present invention also particularly relates to the use of a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of fibrotic diseases, cancer and ocular conditions.

The present invention also more particularly relates to the use of acompound according to formula (I) as described herein for the treatmentor prophylaxis of fibrotic diseases and ocular conditions.

Another embodiment of the present invention is a compound according toformula (I) as described herein for the treatment or prophylaxis ofrenal conditions, liver conditions, inflammatory conditions, conditionsof the nervous system, conditions of the respiratory system, vascularand cardiovascular conditions, fibrotic diseases, cancer, ocularconditions, metabolic conditions, cholestatic and other forms of chronicpruritus and acute and chronic organ transplant rejection.

Another particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis fibrotic diseases, cancer and ocular conditions.

Another more particular embodiment of the present invention is acompound according to formula (I) as described herein for the treatmentor prophylaxis fibrotic diseases and ocular conditions.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis renal conditions, liver conditions,inflammatory conditions, conditions of the nervous system, conditions ofthe respiratory system, vascular and cardiovascular conditions, fibroticdiseases, cancer, ocular conditions, metabolic conditions, cholestaticand other forms of chronic pruritus and acute and chronic organtransplant rejection.

The present invention also particularly relates to the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of fibrotic diseases, cancerand ocular conditions.

The present invention also further particularly relates to the use of acompound according to formula (I) as described herein for thepreparation of a medicament for the treatment or prophylaxis of fibroticdiseases and ocular conditions.

Also an object of the invention is a method for the treatment orprophylaxis of renal conditions, liver conditions, inflammatoryconditions, conditions of the nervous system, conditions of therespiratory system, vascular and cardiovascular conditions, fibroticdiseases, cancer, ocular conditions, metabolic conditions, cholestaticand other forms of chronic pruritus and acute and chronic organtransplant rejection, which method comprises administering an effectiveamount of a compound according to formula (I) as described herein.

Also a particular object of the invention is a method for the treatmentor prophylaxis of fibrotic diseases, cancer and ocular conditions, whichmethod comprises administering an effective amount of a compoundaccording to formula (I) as described herein.

Also a more particular object of the invention is a method for thetreatment or prophylaxis of fibrotic diseases and ocular conditions,which method comprises administering an effective amount of a compoundaccording to formula (I) as described herein.

In a particular embodiment, the renal condition is selected from thegroup consisting of acute kidney injury, chronic kidney disease,diabetic nephropathy, acute kidney transplant rejection and chronicallograft nephropathy.

In another particular embodiment, the renal condition is acute kidneyinjury.

In another particular embodiment, the renal condition is chronic kidneydisease.

In a further particular embodiment, the renal condition is diabeticnephropathy.

In another particular embodiment, the renal condition is acute kidneytransplant rejection.

In another particular embodiment, the renal condition is chronicallograft nephropathy.

In a particular embodiment, the liver condition is acute and chronicliver transplant rejection

In a particular embodiment, the inflammatory condition is arthritis.

In a particular embodiment, the condition of the nervous system isneuropathic pain.

In another embodiment, the fibrotic disease is encapsulating peritonitis

In another embodiment, the fibrotic disease is idiopathic pulmonaryfibrosis.

In another embodiment, the fibrotic disease is non-alcoholic liversteatosis, liver fibrosis or liver cirrhosis.

Also an embodiment of the present invention are compounds of formula (I)as described herein, when manufactured according to any one of thedescribed processes.

Assay Procedures

Production of Human Full Length ATX, with and without His Tag

Autotaxin (ATX-ENPP2) Cloning:

cDNA was prepared from commercial human hematopoietic cells total RNAand used as template in overlapping PCR to generate a full length humanENPP2 ORF with or without a 3′-6×His tag. These full length inserts werecloned into the pcDNA3.1V5-His TOPO (Invitrogen) vector. The DNAsequences of several single clones were verified. The DNA from a correctfull length clone was used to transfect Hek293 cells for verification ofprotein expression. The sequence of the encoded ENPP2 conforms toSwissprot entry Q13822, with or without the additional C-terminal 6×Histag.

ATX Fermentation:

Recombinant protein was produced by large-scale transient transfectionin 20 L controlled stirred tank bioreactors (Sartorius). During cellgrowth and transfection, temperature, stirrer speed, pH and dissolvedoxygen concentration were maintained at 37° C., 120 rpm, 7.1 and 30% DO,respectively. FreeStyle 293-F cells (Invitrogen) were cultivated insuspension in FreeStyle 293 medium (Invitrogen) and transfected at ca.1-1.5×10E6 cells/mL with above plasmid DNAs using X-tremeGENE Ro-1539(commercial product, Roche Diagnostics) as complexing agent. Cells werefed a concentrated nutrient solution (J Immunol Methods 194 (1996), 19,1-199 (page 193)) and induced by sodium butyrate (2 mM) at 72 hpost-transfection and harvested at 96 h post-transfection. Expressionwas analyzed by Western Blot, enzymatic assay and/or analytical IMACchromatography. After cooling the cell suspension to 4° C. in aflow-through heat exchanger, cell separation and sterile filtration ofsupernatant was performed by filtration through Zeta Plus 60M02 E16(Cuno) and Sartopore 2 XLG (Sartorius) filter units. The supernatant wasstored at 4° C. prior to purification.

ATX Purification:

20 liter of culture supernatant were conditioned for ultrafiltration byadding Brij 35 to a final concentration of 0.02% and by adjusting the pHto 7.0 using 1 M HCl. Then the supernatant was first microfiltredthrough a 0.2 μm Ultran-Pilot Open Channel PES filter (Whatman) andafterwards concentrated to 1 liter through an Ultran-Pilot ScreenChannel PES filter with 30 kDa MWCO (Whatman). Prior to IMACchromatography, NiSO₄ was added to a final concentration of 1 mM. Thecleared supernatant was then applied to a HisTrap column (GE Healthcare)previously equilibrated in 50 mM Na₂HPO₄ pH 7.0, 0.5 M NaCl, 10%glycerol, 0.3% CHAPS, 0.02% NaN₃. The column was washed stepwise withthe same buffer containing 20 mM, 40 mM and 50 mM imidazole,respectively. The protein was subsequently eluted using a lineargradient to 0.5 M imidazole in 15 column volumes. ATX containingfractions were pooled and concentrated using an Amicon cell equippedwith a 30 kDa PES filter membrane. The protein was further purified bysize exclusion chromatography on Superdex S-200 prep grade (XK 26/100)(GE Healthcare) in 20 mM BICINE pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3%CHAPS, 0.02% NaN₃. Final yield of protein after purification was 5-10 mgATX per liter of culture supernatant. The protein was stored at −80° C.

Human ATX Enzyme Inhibition Assay

ATX inhibition was measured by a fluorescence quenching assay using aspecifically labeled substrate analogue (MR121 substrate). To obtainthis MR121 substrate, BOC and TBS protected 6-amino-hexanoic acid(R)-3-({2-[3-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-propionylamino]-ethoxy}-hydroxy-phosphoryloxy)-2-hydroxy-propylester (Ferguson et al., Org Lett 2006, 8 (10), 2023) was labeled withMR121 fluorophore (CAS 185308-24-1,1-(3-carboxypropyl)-11-ethyl-1,2,3,4,8,9,10,11-octahydro-dipyrido[3,2-b:2′,3′-i]phenoxazin-13-ium)on the free amine of the ethanolamine side and then, after deprotection,subsequently with tryptophan on the side of the aminohexanoic acid.Assay working solutions were made as follows:Assay buffer (50 mM Tris-HCl, 140 mM NaCl, 5 mM KCl, 1 mM CaCl₂, 1 mMMgCl₂, 0.01% Triton-X-100, pH 8.0;ATX solution: ATX (human His-tagged) stock solution (1.08 mg/mL in 20 mMbicine, pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN₃),diluted to 1.4-2.5× final concentration in assay buffer;MR121 substrate solution: MR121 substrate stock solution (800 μM MR121substrate in DMSO), diluted to 2-5× final concentration in assay buffer.Test compounds (10 mM stock in DMSO, 8 μL) were obtained in 384 wellsample plates (Corning Costar #3655) and diluted with 8 μL DMSO.Row-wise serial dilutions were made by transferring 8 μL cpd solution tothe next row up to row O. The compound and control solutions were mixedfive times and 2 μL were transferred to 384 well assay plates (CorningCostar #3702). Then, 15 μL of 41.7 nM ATX solution was added (30 nMfinal concentration), mixed five times and then incubated for 15 minutesat 30° C. 10 μL of MR121 substrate solution was added (1 μM finalconcentration), mixed 30 times and then incubated for 15 minutes at 30°C. Fluorescence was then measured every 2 minutes for 1 hour (PerkinElmer plate: vision multimode reader); light intensity: 2.5%; exp. time:1.4 sec, Filter: Fluo_630/690 nm) and IC₅₀ values were calculated fromthese readouts.IC₅₀ values for the examples of this invention are given in the tablebelow:

Example IC50 (μM) 1 0.034 1.001 0.011 1.002 0.064 1.003 0.0085 1.0040.017 1.005 0.12 1.006 0.008 1.007 0.062 1.008 0.036 1.009 0.008 1.0100.016 1.011 0.008 1.012 0.086 1.013 0.054 1.014 0.045 1.015 0.011 1.0160.017 1.017 0.008 1.018 0.016 1.019 0.0115 1.020 0.006 1.021 0.265 1.0220.155 1.023 1.473 1.024 0.377 1.025 0.0085 1.026 0.0115 1.027 0.8281.028 2.834 1.029 0.07 1.030 0.104 1.031 0.224 1.032 0.013 1.033 0.1041.034 0.489 1.035 0.243 1.036 0.13 1.037 0.1587 1.038 0.687 1.039 3.331.040 8.674 1.041 0.538 1.042 0.632 1.043 1.406 1.044 0.013 1.045 0.0111.046 0.028 1.047 0.205 1.048 0.208 1.049 0.004 1.050 0.008 1.051 0.0071.052 0.0035 1.053 0.014 1.054 0.0592 1.055 0.022 1.056 0.029 1.0570.0077 1.058 0.0053 1.059 0.0013 1.060 0.0047 1.061 0.0405 1.062 0.0091.063 0.001 1.064 0.001 1.065 0.0065 1.066 0.005 1.067 0.005 1.0680.0143 1.069 0.008 1.070 0.004 1.071 0.0035 1.072 0.006 1.073 0.00351.074 0.005 1.075 0.02 1.076 0.0125 1.077 0.0075 1.078 0.0035 1.0790.0315 1.080 0.0025 1.081 0.0075 1.082 0.003 1.083 0.1535 1.084 0.0051.085 0.0027 1.086 0.017 1.087 0.0153 1.088 0.0413 1.089 0.02 1.0900.019 1.091 0.017 1.092 0.018 1.093 0.017 1.094 0.077 1.095 0.032 1.0960.012 1.097 0.025 1.098 0.859 1.099 0.277 1.100 0.01 1.101 4.433 1.1020.992 1.103 0.027 1.104 0.01 1.105 0.008 1.106 0.169 1.107 0.141 1.1080.006 1.109 0.301 1.110 0.0325 1.111 0.3305 2 0.014 2.001 0.0045 3 0.1733.001 0.232 4 0.07

Compounds of formula (I) and their pharmaceutically acceptable salts oresters thereof as described herein have IC₅₀ values between 0.00001 μMand 1000 μM, particular compounds have IC₅₀ values between 0.0005 μM and500 μM, further particular compounds have IC₅₀ values between 0.0005 μMand 50 μM, more particular compounds have IC₅₀ values between 0.0005 μMand 5 μM. These results have been obtained by using the enzymatic assaydescribed above.

The compounds of formula (I) and their pharmaceutically acceptable saltscan be used as medicaments (e.g. in the form of pharmaceuticalpreparations). The pharmaceutical preparations can be administeredinternally, such as orally (e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions), nasally (e.g. in the form of nasal sprays) or rectally(e.g. in the form of suppositories). However, the administration canalso be effected parenterally, such as intramuscularly or intravenously(e.g. in the form of injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable saltscan be processed with pharmaceutically inert, inorganic or organicadjuvants for the production of tablets, coated tablets, dragées andhard gelatin capsules. Lactose, corn starch or derivatives thereof,talc, stearic acid or its salts etc. can be used, for example, as suchadjuvants for tablets, dragées and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, in the caseof oral administration a daily dosage of about 0.1 mg to 20 mg per kgbody weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g.about 300 mg per person), divided preferably into 1-3 individual doses,which can consist, for example, of the same amounts, should it beappropriate. It will, however, be clear that the upper limit givenherein can be exceeded when this is shown to be indicated.

The invention is illustrated hereinafter by Examples, which have nolimiting character.

In case the preparative examples are obtained as a mixture ofenantiomers, the pure enantiomers can be obtained by methods describedherein or by methods known to those skilled in the art, such as e.g.chiral chromatography or crystallization.

EXAMPLES

All examples and intermediates were prepared under nitrogen atmosphereif not specified otherwise.

ABBREVIATIONS

aq.=aqueous; CAS-RN=Chemical Abstracts Service Registry Number;e.r.=enantiomeric ratio; HPLC=high performance liquid chromatography;MS=mass spectrum; NMR=nuclear magnetic resonance spectrum;sat.=saturated

Example 1[(3aS,3bS,6aR,6bR)-5-(1H-Benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-naphthalen-2-yl)-methanone

To a solution of(3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole(intermediate 1; 30 mg, 217 μmol) in N,N-dimethylformamide (3.5 ml) wereadded N-methylmorpholine (110 mg, 1.09 mmol),6-chloro-naphthalene-2-carboxylic acid (CAS-RN 5042-97-7; 44.9 mg, 217μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (82.5 mg, 217 μmol). After stirring for 8 h at roomtemperature 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (35.4 mg, 217μmol, Eq: 1.00) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (82.5 mg, 217 μmol) were added, then after 16 h thereaction mixture was partitioned between sat. aq. ammonium chloridesolution and ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, filtered and evaporated. Chromatography(silica gel; gradient dichloromethane to dichloromethane/methanol/25%aq. ammonia solution 90:10:0.25) produced the title compound (51 mg,50%). Off-white solid, MS: 472.5 (M+H)⁺.

The following examples were produced in analogy to example 1, replacing6-chloro-naphthalene-2-carboxylic acid and1H-benzo[d][1,2,3]triazole-5-carboxylic acid by carboxylic acid 1 andcarboxylic acid 2, respectively.

carboxylic carboxylic MS, Ex. Systematic Name acid 1 acid 2 m/e 1.0011-[(3aS,3bR,6aS,6bR)-5-(1H- 4-(trifluoro- 1H-benzo[d]- 500.6benzotriazole-5-carbonyl)-octahydro- methoxy)- [1,2,3]triazole- (M + H)⁺cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4- hydrocinnamic 5-carboxylictrifluoromethoxy-phenyl)-propan-1-one acid (CAS-RN acid

886499-74-7) 1.002 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-4′-fluorobiphenyl- 1H-benzo[d]- 482.55-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- 4-carboxylic acid[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(4′-fluoro-biphenyl-4-yl)-(CAS-RN 5731- 5-carboxylic methanone 10-2) acid

1.003 (E)-1-[(3aS,3bR,6aS,6bR)-5-(1H- 4-(trifluoro- 1H-benzo[d]- 498.5benzotriazole-5-carbonyl)-octahydro- methoxy)- [1,2,3]triazole- (M + H)⁺cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4- cinnamic acid 5-carboxylictrifluoromethoxy-phenyl)-propenone (CAS-RN acid

199679-35-1) 1.004 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 6-bromo-2-1H-benzo[d]- 514.8 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- naphthoicacid [1,2,3]triazole- (M − H)⁻ c′]dipyrrol-2-yl]-(6-bromo-naphthalen-2-(CAS-RN 5773- 5-carboxylic yl)-methanone 80-8) acid

1.005 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 6-methoxy-2- 1H-benzo[d]-468.7 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- naphthoic acid[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(6-methoxy-naphthalen-2-(CAS-RN 2471- 5-carboxylic yl)-methanone 70-7) acid

1.006 (E)-1-[(3aS,3bS,6aR,6bR)-5-((R)-4,5,6,7- 4-(trifluoro- (+)-(R)-502.7 tetrahydro-1H-benzotriazole-5-carbonyl)- methoxy)- 4,5,6,7- (M +H)⁺ octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol cinnamic acidtetrahydro-1H- 2-yl]-3-(4-trifluoromethoxy-phenyl)- (CAS-RN benzo[d]-propenone 199679-35-1) [1,2,3]triazole-

5-carboxylic acid (intermediate 11) 1.007 6-[(3aS,3bS,6aR,6bR)-5-(1H-6-cyano-2- 1H-benzo[d]- 463.5 benzotriazole-5-carbonyl)-octahydro-naphthoic acid [1,2,3]triazole- (M + H)⁺cyclobuta[1,2-c;3,4-c′]dipyrrole-2- (CAS-RN 5159- 5-carboxyliccarbonyl]-naphthalene-2-carbonitrile 60-4) acid

1.008 1-[(3aR,3bS,6aR,6bS)-5-(1H- 2-(4-(trifluoro- 1H-benzo[d]- 502.4benzotriazole-5-carbonyl)-octahydro- methoxy)- [1,2,3]triazole- (M + H)⁺cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-2-(4- phenoxy)acetic 5-carboxylictrifluoromethoxy-phenoxy)-ethanone acid (CAS-RN acid

72220-50-9) 1.009 1-[(3aR,3bS,6aR,6bS)-5-(1H- 2-(2-isopropyl-1H-benzo[d]- 460.4 benzotriazole-5-carbonyl)-octahydro- phenoxy)acetic[1,2,3]triazole- (M + H)⁺ cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-2-(2-acid (CAS-RN 5-carboxylic isopropyl-phenoxy)-ethanone 25141-58-6) acid

1.010 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 5-(trifluoro- 1H-benzo[d]-511.0 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- methoxy)-1H-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(5-trifluoromethoxy-1H-indole-2- 5-carboxylic indol-2-yl)-methanone carboxylic acid acid

(CAS-RN 175203-84-6) 1.011 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-6-(trifluoro- 1H-benzo[d]- 511.75-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- methoxy)-1H- [1,2,3]triazole-(M + H)⁺ c′]dipyrrol-2-yl]-(6-trifluoromethoxy-1H- indole-2-5-carboxylic indol-2-yl)-methanone carboxylic acid acid

(CAS-RN 923259-70-5) 1.012 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-2-naphthoic acid 1H-benzo[d]- 438.75-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- (CAS-RN 93-09-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-naphthalen-2-yl- 4)5-carboxylic methanone acid

1.013 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 6-methyl-2- 1H-benzo[d]-452.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- naphthoic acid[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(6-methyl-naphthalen-2-(CAS-RN 5774- 5-carboxylic yl)-methanone 08-3) acid

1.014 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 7-methyl-2- 1H-benzo[d]-452.7 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- naphthoic acid[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(7-methyl-naphthalen-2-(CAS-RN 5159- 5-carboxylic yl)-methanone 64-8) acid

1.015 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 6-phenyl-2- 1H-benzo[d]-514.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- naphthoic acid[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(6-phenyl-naphthalen-2-(CAS-RN 5-carboxylic yl)-methanone 855207-53-3) acid

1.016 (6-bromo-naphthalen-2-yl)- 6-bromo-2- (+)-(R)- 520.5[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- naphthoic acid 4,5,6,7- (M + H)⁺tetrahydro-1H-benzotriazole-5-carbonyl)- (CAS-RN 5773- tetrahydro-1H-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- 80-8) benzo[d]-2-yl]-methanone [1,2,3]triazole-

5-carboxylic acid (intermediate 11) 1.017[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 4′-chlorobiphenyl- 1H-benzo[d]-498.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- 4-carboxylic acid[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(4′-chloro-biphenyl-4-yl)-(CAS-RN 5748- 5-carboxylic methanone 41-4) acid

1.018 (4′-chlorobiphenyl-4-yl)- 4′-chlorobiphenyl- (+)-(R)- 502.5[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- 4-carboxylic acid 4,5,6,7- (M + H)⁺tetrahydro-1H-benzotriazole-5-carbonyl)- (CAS-RN 5748- tetrahydro-1H-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- 41-4) benzo[d]-2-yl]-methanone [1,2,3]triazole-

5-carboxylic acid (intermediate 11) 1.019[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- 5-(trifluoro- (+)-(R)- 515.7tetrahydro-1H-benzotriazole-5-carbonyl)- methoxy)-1H- 4,5,6,7- (M + H)⁺octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- indole-2- tetrahydro-1H-2-yl]-(5-trifluoromethoxy-1H-indol-2-yl)- carboxylic acid benzo[d]-methanone (CAS-RN [1,2,3]triazole-

175203-84-6) 5-carboxylic acid (intermediate 11) 1.020[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- 6-(trifluoro- (+)-(R)- 515.7tetrahydro-1H-benzotriazole-5-carbonyl)- methoxy)-1H- 4,5,6,7- (M + H)⁺octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- indole-2- tetrahydro-1H-2-yl]-(6-trifluoromethoxy-1H-indol-2-yl)- carboxylic acid benzo[d]-methanone (CAS-RN [1,2,3]triazole-

923259-70-5) 5-carboxylic acid (intermediate 11) 1.021[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 3-methoxy-2- 1H-benzo[d]- 468.65-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- naphthoic acid[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(3-methoxy-naphthalen-2-(CAS-RN 883-62- 5-carboxylic yl)-methanone 5) acid

1.022 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 1-methoxy-2- 1H-benzo[d]-468.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- naphthoic acid[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(1-methoxy-naphthalen-2-(CAS-RN 883-21- 5-carboxylic yl)-methanone 6) acid

1.023 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 1H-indole-2- 1H-benzo[d]-427.5 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- carboxylic acid[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(1H-indol-2-yl)- (CAS-RN1477- 5-carboxylic methanone 50-5) acid

1.024 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 1-methyl-1H- 1H-benzo[d]-441.5 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- indole-2-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(1-methyl-1H-indol-2-yl)-carboxylic acid 5-carboxylic methanone (CAS-RN 16136- acid

58-6) 1.025 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 4-(cyclopropyl-1H-benzo[d]- 508.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-methoxy)-2- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-(4-cyclopropylmethoxy- naphthoic acid 5-carboxylicnaphthalen-2-yl)-methanone acid

1.026 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 4-methoxy-2- 1H-benzo[d]-468.5 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- naphthoic acid[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(4-methoxy-naphthalen-2-(CAS-RN 5773- 5-carboxylic yl)-methanone 93-3) acid

1.027 2-[(3aR,3bS,6aR,6bS)-5-(1H- 5-cyano-1H- 1H-benzo[d]- 452.6benzotriazole-5-carbonyl)-octahydro- indole-2- [1,2,3]triazole- (M + H)⁺cyclobuta[1,2-c;3,4-c′]dipyrrole-2- carboxylic acid 5-carboxyliccarbonyl]-1H-indole-5-carbonitrile (CAS-RN acid

169463-44-9) 1.028 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 3-methoxy-1H-benzo[d]- 418.5 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- benzoicacid [1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(3-methoxy-phenyl)-(CAS-RN 586-38- 5-carboxylic methanone 9) acid

1.029 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 4-methoxy-2- 1H-benzo[d]-469.5 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- quinoline-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(4-methoxy-quinolin-2-carboxylic acid 5-carboxylic yl)-methanone (CAS-RN 15733- acid

83-2) 1.030 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 2-(4- 1H-benzo[d]-503.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- chlorophenyl)-5-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-[2-(4-chloro-phenyl)-5-methyl-1,3- 5-carboxylic methyl-oxazol-4-yl]-methanone oxazole-4- acid

carboxylic acid (CAS-RN 2940- 23-0) 1.031[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole- 1,2,3,4- 1H-benzo[d]- 442.75-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- tetrahydro-2-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(1,2,3,4-tetrahydro-naphthoic acid 5-carboxylic naphthalen-2-yl)-methanone (CAS-RN 53440-acid

12-3) 1.032 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 1-methyl-5-1H-benzo[d]- 525.7 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-(trifluoro- [1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(1-methyl-5-methoxy)-1H- 5-carboxylic trifluoromethoxy-1H-indol-2-yl)- indole-2-acid methanone carboxylic acid

(CAS-RN 1257122-42-1) 1.033 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-6-chloro-1H- 1H-benzo[d]- 461.65-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- indole-2- [1,2,3]triazole-(M + H)⁺ c′]dipyrrol-2-yl]-(6-chloro-1H-indol-2-yl)- carboxylic acid5-carboxylic methanone (CAS-RN 16732- acid

75-5) 1.034 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 6-chloro-1-1H-benzo[d]- 475.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- methyl-1H-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(6-chloro-1-methyl-1H-indole-2- 5-carboxylic indol-2-yl)-methanone carboxylic acid acid

1.035 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 6-methyl-1H- 1H-benzo[d]-441.7 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- indole-2-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(6-methyl-1H-indol-2-yl)-carboxylic acid 5-carboxylic methanone (CAS-RN 18474- acid

59-4) 1.036 {2-[(3aR,3bS,6aR,6bS)-5-(1H- 1-(cyanomethyl)- 1H-benzo[d]-466.6 benzotriazole-5-carbonyl)-octahydro- 1H-indole-2- [1,2,3]triazole-(M + H)⁺ cyclobuta[1,2-c;3,4-c′]dipyrrole-2- carboxylic acid5-carboxylic carbonyl]-indol-1-yl}-acetonitrile (CAS-RN acid

959089-89-5) 1.037 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-1-isobutyl-1H- 1H-benzo[d]- 483.75-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- indole-2- [1,2,3]triazole-(M + H)⁺ c′]dipyrrol-2-yl]-(1-isobutyl-1H-indol-2- carboxylic acid5-carboxylic yl)-methanone (CAS-RN acid

1020986-39-3) 1.038 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- quinaldicacid 1H-benzo[d]- 439.5 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-(CAS-RN 93-10- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-quinolin-2-yl-methanone 7) 5-carboxylic

acid 1.039 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- isoquinoline-3-1H-benzo[d]- 439.5 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- carboxylicacid [1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-isoquinolin-3-yl-(CAS-RN 6624- 5-carboxylic methanone 49-3) acid

1.040 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- indole-6- 1H-benzo[d]-427.7 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- carboxylic acid[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(1H-indol-6-yl)- (CAS-RN1670- 5-carboxylic methanone 82-2) acid

1.041 3-[(3aS,3bR,6aS,6bR)-5-(1H- 4-oxo-1,2,3,4- 1H-benzo[d]- 456.5benzotriazole-5-carbonyl)-octahydro- tetrahydro- [1,2,3]triazole- (M +H)⁺ cyclobuta[1,2-c;3,4-c′]dipyrrole-2- naphthalene-2- 5-carboxyliccarbonyl]-3,4-dihydro-2H-naphthalen-1- carboxylic acid acid one (CAS-RN6566-

40-1) 1.042 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- chroman-2-1H-benzo[d]- 444.7 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- carboxylicacid [1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-chroman-2-yl-methanone(CAS-RN 51939- 5-carboxylic

71-0) acid 1.043 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- indole-5-1H-benzo[d]- 427.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- carboxylicacid [1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(1H-indol-5-yl)-(CAS-RN 1670- 5-carboxylic methanone 81-1) acid

1.044 (4-methoxy-naphthalen-2-yl)- 4-methoxy-2- (+)-(R)- 472.7[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- naphthoic acid 4,5,6,7- (M + H)⁺tetrahydro-1H-benzotriazole-5-carbonyl)- (CAS-RN 5773- tetrahydro-1H-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- 93-3) benzo[d]-2-yl]-methanone [1,2,3]triazole-

5-carboxylic acid (intermediate 11) 1.045[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 6-(4- 1H-benzo[d]- 499.45-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- chlorophenyl)-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-[6-(4-chloro-phenyl)-nicotinic acid 5-carboxylic pyridin-3-yl]-methanone (CAS-RN 31676- acid

66-1) 1.046 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 1-methoxyiso-1H-benzo[d]- 469.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-quinoline-3- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-(1-methoxy-isoquinolin-3- carboxylic acid 5-carboxylicyl)-methanone (CAS-RN acid 1094553-95-3)

1.047 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 4- 1H-benzo[d]- 453.55-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- methylquinoline-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(4-methyl-quinolin-2-yl)-2-carboxylic acid 5-carboxylic methanone (CAS-RN 40609- acid

76-5) 1.048 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 5-chloroindole-2-1H-benzo[d]- 461.4 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- carboxylicacid [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-(5-chloro-1H-indol-2-yl)- (CAS-RN 10517- 5-carboxylicmethanone 21-2) acid

1.049 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 4-(2- 1H-benzo[d]- 512.45-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- methoxyethoxy)-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-2-naphthoic acid 5-carboxylic naphthalen-2-yl]-methanone acid

1.050 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 7-phenyl- 1H-benzo[d]-514.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- naphthalene-2-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(7-phenyl-naphthalen-2-carboxylic acid 5-carboxylic yl)-methanone (CAS-RN acid

229006-56-8) 1.051 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 4-ethoxy-1H-benzo[d]- 482.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-naphthalene-2- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-(4-ethoxy-naphthalen-2- carboxylic acid 5-carboxylicyl)-methanone (CAS-RN acid

1368864-77-0) 1.052 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-4-isopropoxy- 1H-benzo[d]- 496.55-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- naphthalene-2-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(4-isopropoxy- carboxylicacid 5-carboxylic naphthalen-2-yl)-methanone (CAS-RN acid

1368865-02-4) 1.053 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-4-benzyloxy-1H- 1H-benzo[d]- 533.45-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- indole-6- [1,2,3]triazole-(M + H)⁺ c′]dipyrrol-2-yl]-(4-benzyloxy-1H-indol-6- carboxylic acid5-carboxylic yl)-methanone (CAS-RN acid

105265-24-5) 1.054 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 5,6,7,8-1H-benzo[d]- 442.5 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-tetrahydro-2- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-(5,6,7,8-tetrahydro- naphthoic acid 5-carboxylicnaphthalen-2-yl)-methanone (CAS-RN 1131- acid

63-1) 1.055 [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole- 4,4-dimethyl-1H-benzo[d]- 470.7 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- 1,2,3,4-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(4,4-dimethyl-1,2,3,4-tetrahydro- 5-carboxylic tetrahydro-naphthalen-2-yl)-methanonenaphthalene-2- acid

carboxylic acid (CAS-RN 23204- 02-6) 1.056[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole- 1-(3- 1H-benzo[d]- 515.55-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- methoxypropyl)-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-[1-(3-methoxy-propyl)-1,2,3,4- 5-carboxylic 1,2,3,4-tetrahydro-quinolin-3-yl]- tetrahydro-acid methanone quinoline-3-

carboxylic acid (intermediate 6) 1.057[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 1-(2- 1H-benzo[d]- 513.55-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- methoxyethoxy)-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-[1-(2-methoxy-ethoxy)-isoquinoline-3- 5-carboxylic isoquinolin-3-yl]-methanone carboxylic acidacid

(CAS-RN 1094758-42-5) 1.058 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-1-(cyclopropyl- 1H-benzo[d]- 509.55-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- methoxy)iso- [1,2,3]triazole-(M + H)⁺ c′]dipyrrol-2-yl]-(1-cyclopropylmethoxy- quinoline-3-5-carboxylic isoquinolin-3-yl)-methanone carboxylic acid acid

(CAS-RN 1097166-34-1) 1.059 (4-isopropoxy-naphthalen-2-yl)-4-isopropoxy- (+)-(R)- 500.7 [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-naphthalene-2- 4,5,6,7- (M + H)⁺tetrahydro-1H-benzotriazole-5-carbonyl)- carboxylic acid tetrahydro-1H-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- (CAS-RN benzo[d]-2-yl]-methanone 1368865-02-4) [1,2,3]triazole-

5-carboxylic acid (intermediate 11) 1.060[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 1-(2,2,2- 1H-benzo[d]- 537.65-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- trifluoroethoxy)-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-[1-(2,2,2-trifluoro-isoquinoline-3- 5-carboxylic ethoxy)-isoquinolin-3-yl]-methanonecarboxylic acid acid

(CAS-RN 1096982-79-4) 1.061 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-4-isopropoxy-1H- 1H-benzo[d]- 485.45-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- indole-6- [1,2,3]triazole-(M + H)⁺ c′]dipyrrol-2-yl]-(4-isopropoxy-1H-indol- carboxylic acid5-carboxylic 6-yl)-methanone (intermediate 3.3) acid

1.062 4-[(3aS,3bS,6aR,6bR)-5-(4-isopropoxy- 4-isopropoxy- 4-sulfamoyl-534.6 naphthalene-2-carbonyl)-octahydro- naphthalene-2- benzoic acid(M + H)⁺ cyclobuta[1,2-c;3,4-c′]dipyrrole-2- carboxylic acidcarbonyl]benzenesulfonamide (CAS-RN

1368865-02-4) 1.063 [6-(4-chloro-phenyl)-pyridin-3-yl]- 6-(4- (+)-(R)-503.4 [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- chlorophenyl)- 4,5,6,7- (M +H)⁺ tetrahydro-1H-benzotriazole-5-carbonyl)- nicotinic acidtetrahydro-1H- octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- (CAS-RN 31676-benzo[d]- 2-yl]-methanone 66-1) [1,2,3]triazole-

5-carboxylic acid (intermediate 11) 1.064(1-cyclopropylmethoxy-isoquinolin-3-yl)- 1-(cyclopropyl- (+)-(R)- 513.7[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- methoxy)iso- 4,5,6,7- (M + H)⁺tetrahydro-1H-benzotriazole-5-carbonyl)- quinoline-3- tetrahydro-1H-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- carboxylic acid benzo[d]-2-yl]-methanone (CAS-RN [1,2,3]triazole-

1097166-34-1) 5-carboxylic acid (intermediate 11) 1.065[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 4-isopropoxy-1- 1H-benzo[d]-499.7 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- methyl-1H-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(4-isopropoxy-1-methyl-indole-6- 5-carboxylic 1H-indol-6-yl)-methanone carboxylic acid acid

(intermediate 10) 1.066 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 4-1H-benzo[d]- 483.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-ethoxyquinoline- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-(4-ethoxy-quinolin-2-yl)- 2-carboxylic acid5-carboxylic methanone (CAS-RN 40609- acid

78-7) 1.067 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 4-isopropoxy-1H-benzo[d]- 497.4 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-quinoline-2- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-(4-isopropoxy-quinolin-2- carboxylic acid 5-carboxylicyl)-methanone (CAS-RN acid

1406553-19-2) 1.068 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 6-chloro-9H-1H-benzo[d]- 511.6 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-carbazole-2- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-(6-chloro-9H-carbazol-2- carboxylic acid 5-carboxylicyl)-methanone (CAS-RN 58479- acid

49-5) 1.069 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 4-(2-methoxy-1H-benzo[d]- 513.4 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-ethoxy)quinoline- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)- 2-carboxylic acid 5-carboxylicquinolin-2-yl]-methanone (CAS-RN 52144- acid

36-2) 1.070 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 4-isopropoxy-7-1H-benzo[d]- 565.4 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-(trifluoro- [1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(4-isopropoxy-7-methyl)quinoline- 5-carboxylic trifluoromethyl-quinolin-2-yl)-methanone2-carboxylic acid acid

(intermediate 2) 1.071 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-4-(cyclopropyl- 1H-benzo[d]- 509.65-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- methoxy)- [1,2,3]triazole-(M + H)⁺ c′]dipyrrol-2-yl]-(4-cyclopropylmethoxy- quinoline-2-5-carboxylic quinolin-2-yl)-methanone carboxylic acid acid

(CAS-RN 1275281-11-2) 1.072 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-(4- 1H-benzo[d]- 499.4 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-chlorophenyl)- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-[5-(4-chloro-phenyl)- picolinic acid 5-carboxylicpyridin-2-yl]-methanone (CAS-RN 87789- acid

85-3) 1.073 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole- 1-ethoxyiso-1H-benzo[d]- 483.4 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-quinoline-3- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-(1-ethoxy-isoquinolin-3- carboxylic acid 5-carboxylicyl)-methanone (CAS-RN acid

1094758-39-0) 1.074 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 1-ethyl-4-1H-benzo[d]- 513.7 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-isopropoxy-1H- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-(1-ethyl-4-isopropoxy- indole-6- 5-carboxylic1H-indol-6-yl)-methanone carboxylic acid acid

(intermediate 2.6) 1.075 6-[(3aR,3bS,6aR,6bS)-5-(1H- 5-(4- 1H-benzo[d]-515.6 benzotriazole-5-carbonyl)-octahydro- chlorophenyl)-6-[1,2,3]triazole- (M + H)⁺ cyclobuta[1,2-c;3,4-c′]dipyrrole-2- oxo-1,6-5-carboxylic carbonyl]-3-(4-chloro-phenyl)-1H-pyridin- dihydropyridine-acid 2-one 2-carboxylic acid

(intermediate 3.2) 1.076 [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-7-chloro-4- 1H-benzo[d]- 517.4 5-carbonyl)-octahydro-cyclobutaethoxyquinoline- [1,2,3]triazole- (M + H)⁺[1,2-c;3,4-c′]dipyrrol-2-yl]-(7-chloro-4- 2-carboxylic acid 5-carboxylicethoxy-quinolin-2-yl)-methanone (intermediate 2.5) acid

1.077 (7-chloro-4-ethoxy-quinolin-2-yl)- 7-chloro-4- (+)-(R)- 521.4[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- ethoxyquinoline- 4,5,6,7- (M + H)⁺tetrahydro-1H-benzotriazole-5-carbonyl)- 2-carboxylic acidtetrahydro-1H- octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- (intermediate2.5) benzo[d]- 2-yl]methanone [1,2,3]triazole-

5-carboxylic acid (intermediate 11) 1.078[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 5,6,7,8- 1H-benzo[d]- 500.75-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- tetrahydro-2-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(4-isopropoxy-5,6,7,8-naphthoic acid 5-carboxylic tetrahydro-naphthalen-2-yl)-methanone(intermediate 2.4) acid

1.079 (1H-benzotriazol-5-yl)- 4-(2- 1H-benzo[d]- 581.7{(3aS,3bR,6aS,6bR)-5-[4-(2-methoxy- methoxyethoxy)- [1,2,3]triazole-(M + H)⁺ ethoxy)-7-trifluoromethyl-quinoline-2- 7-(trifluoro-5-carboxylic carbonyl]-octahydro-cyclobuta[1,2-c;3,4- methyl)quinoline-acid c′]dipyrrol-2-yl}-methanone 2-carboxylic acid

(intermediate 2.3) 1.080 (1H-benzotriazol-5-yl)- 4-ethoxy-6-1H-benzo[d]- 551.6 [(3aS,3bR,6aS,6bR)-5-(4-ethoxy-6- (trifluoromethyl)-[1,2,3]triazole- (M + H)⁺ trifluoromethyl-quinoline-2-carbonyl)-quinoline- 5-carboxylic octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-carboxylic acid acid 2-yl]-methanone (intermediate 2.2)

1.081 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 4-ethoxy-1-ethyl-1H-benzo[d]- 499.5 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-1H-indole-6- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-(4-ethoxy-1-ethyl-1H- carboxylic acid 5-carboxylicindol-5-yl)-methanone (intermediate 3.1) acid

1.082 [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole- 1-ethyl-4-(2,2,2-1H-benzo[d]- 553.4 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-trifluoroethoxy)- [1,2,3]triazole- (M + H)⁺c′]dipyrrol-2-yl]-[1-ethyl-4-(2,2,2-trifluoro- 1H-indole-6- 5-carboxylicethoxy)-1H-indol-5-yl]-methanone carboxylic acid acid

(intermediate 2.1) 1.083 5-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy- 4-6-sulfamoyl- 522.4 quinoline-2-carbonyl)-octahydro- ethoxyquinoline-nicotinic acid (M + H)⁺ cyclobuta[1,2-c;3,4-c′]dipyrrole-2- 2-carboxylicacid (CAS-RN carbonyl]-pyridine-2-sulfonic acid amide (CAS-RN 40609-285135-56-0)

78-7) 1.084 (1H-benzotriazol-5-yl)- 4-(2,2,2- 1H-benzo[d]- 537.4{(3aS,3bR,6aS,6bR)-5-[4-(2,2,2-trifluoro- trifluoroethoxy)-[1,2,3]triazole- (M + H)⁺ ethoxy)-quinoline-2-carbonyl]-octahydro-quinoline-2- 5-carboxylic cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-carboxylic acid acid methanone (CAS-RN

1281584-65-3) 1.085 (1H-benzotriazol-5-yl)- 4-ethoxy-1-(2,2,2-1H-benzo[d]- 553.4 {(3aS,3bS,6aR,6bR)-5-[4-ethoxy-1-(2,2,2-trifluoroethyl)- [1,2,3]triazole- (M + H)⁺trifluoro-ethyl)-1H-indole-6-carbonyl]- 1H-indole-6- 5-carboxylicoctahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- carboxylic acid acid2-yl}-methanone (intermediate 2.9)

1.086 (1H-benzotriazol-5-yl)- 5-chloro-4- 1H-benzo[d]- 493.4[(3aS,3bR,6aS,6bR)-5-(5-chloro-4- (cyclopropyl- [1,2,3]triazole- (M +H)⁺ cyclopropylmethoxy-pyridine-2-carbonyl)- methoxy)picolinic5-carboxylic octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- acid acid2-yl]-methanone

1.087 (1H-benzotriazol-5-yl)- 5-cyclopropyl-6- 1H-benzo[d]- 499.4[(3aS,3bR,6aS,6bR)-5-(5-cyclopropyl-6- (cyclopropyl- [1,2,3]triazole-(M + H)⁺ cyclopropylmethoxy-pyridine-2-carbonyl)- methoxy)picolinic5-carboxylic octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- acid (CAS-RNacid 2-yl]-methanone 1415898-71-3)

1.088 (3,4-dimethyl-phenyl)- 4-ethoxy-5,6,7,8- 1H-benzo[d]- 487.7[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-5,6,7,8- tetrahydro- [1,2,3]triazole-(M + H)⁺ tetrahydro-quinoline-2-carbonyl)- quinoline-2- 5-carboxylicoctahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- carboxylic acid acid2-yl]-methanone (intermediate 8)

1.089 (1H-benzotriazol-5-yl)- 4′-chlorobiphenyl- 1H-benzo[d]- 498.6[(3aS,3bS,6aR,6bR)-5-(4′-chloro-biphenyl- 3-carboxylic acid[1,2,3]triazole- (M + H)⁺ 3-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-(CAS-RN 4655- 5-carboxylic c′]dipyrrol-2-yl]-methanone 10-1) acid

1.090 (1H-benzotriazol-5-yl)- 4-ethoxy-7- 1H-benzo[d]- 513.4[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-7- methoxy- [1,2,3]triazole- (M + H)⁺methoxy-quinoline-2-carbonyl)-octahydro- quinoline-2- 5-carboxyliccyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]- carboxylic acid acid methanone(intermediate 2.8)

1.091 [(3aS,3bS,6aR,6bR)-5-(4-ethoxy-6- 4-ethoxy-6- 1H-[1,2,3]tri- 552.4trifluoromethyl-quinoline-2-carbonyl)- (trifluoromethyl)- azolo[4,5-(M + H)⁺ octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- quinoline-2-b]pyridine-5- 2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5- carboxylic acidcarboxylic acid yl)-methanone (intermediate 2.2) (CAS-RN

1216149-55-1) 1.092 [(3aS,3bS,6aR,6bR)-5-(1-ethoxy- 1-ethoxyiso-1H-[1,2,3]tri- 484.6 isoquinoline-3-carbonyl)-octahydro- quinoline-3-azolo[4,5- (M + H)⁺ cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-carboxylic acid b]pyridine-5- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-(CAS-RN carboxylic acid methanone 1094758-39-0) (CAS-RN

1216149-55-1) 1.093 (1H-benzotriazol-5-yl)- 6-(cyclopropyl- 1H-benzo[d]-527.4 [(3aS,3bR,6aS,6bR)-5-(6- methoxy)-5- [1,2,3]triazole- (M + H)⁺cyclopropylmethoxy-5-trifluoromethyl- (trifluoromethyl)- 5-carboxylicpyridine-2-carbonyl)-octahydro- picolinic acid acidcyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]- (CAS-RN methanone 1415899-19-2)

1.094 (1H-benzotriazol-5-yl)- 5-cyclopropyl-4- 1H-benzo[d]- 527.4{(3aS,3bR,6aS,6bR)-5-[5-cyclopropyl-4- (2,2,2- [1,2,3]triazole- (M + H)⁺(2,2,2-trifluoro-ethoxy)-pyridine-2- trifluoroethoxy)- 5-carboxyliccarbonyl]-octahydro-cyclobuta[1,2-c;3,4- picolinic acid acidc′]dipyrrol-2-yl}-methanone

1.095 (1H-benzotriazol-5-yl)-{(3aS,3bR,6a[6- 6-cyclopropyl-5-1H-benzo[d]- 528.4 cyclopropyl-5-(2,2,2-trifluoro-ethoxy)- (2,2,2-[1,2,3]triazole- (M + H)⁺ pyridazine-3-carbonyl]-octahydro-trifluoroethoxy)- 5-carboxylic cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-pyridazine-3- acid methanone′]dipyrrol-2-yl}-methanone carboxylic acid

1.096 [(3aR,3bS,6aR,6bS)-5-(2H-benzotriazole- 6-chloro-4- 1H-benzo[d]-517.4 5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4- ethoxyquinoline-[1,2,3]triazole- (M + H)⁺ c′]dipyrrol-2-yl]-(6-chloro-4-ethoxy-2-carboxylic acid 5-carboxylic quinolin-2-yl)-methanone (CAS-RN acid

1355234-15-9) 1.097 (1H-benzotriazol-5-yl)- 6-(2,2,2- 1H-benzo[d]- 555.4{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-trifluoro- trifluoroethoxy)-[1,2,3]triazole- (M + H)⁺ ethoxy)-5-trifluoromethyl-pyridine-2- 5-5-carboxylic carbonyl]-octahydro-cyclobuta[1,2-c;3,4- (trifluoromethyl)-acid c′]dipyrrol-2-yl}-methanone picolinic acid

1.098 (1H-benzotriazol-5-yl)- 6-(2,2,2- 1H-benzo[d]- 487.7{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-trifluoro- trifluoroethoxy)-[1,2,3]triazole- (M + H)⁺ ethoxy)-pyridine-2-carbonyl]-octahydro-picolinic acid 5-carboxylic cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-(CAS-RN acid methanone 1247503-48-5)

1.099 (1H-benzotriazol-5-yl)- 6-(2,2,2- 1H-benzo[d]- 487.7{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro- trifluoroethoxy)-[1,2,3]triazole- (M + H)⁺ ethoxy)-pyridine-3-carbonyl]-octahydro-nicotinic acid 5-carboxylic cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-(CAS-RN acid methanone 175204-90-7)

1.100 (1H-benzotriazol-5-yl)- 5-bromo-6-(2,2,2- 1H-benzo[d]- 565.5{(3aS,3bS,6aR,6bR)-5-[5-bromo-6-(2,2,2- trifluoroethoxy)-[1,2,3]triazole- (M + H)⁺ trifluoro-ethoxy)-pyridine-3-carbonyl]-nicotinic acid 5-carboxylic octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-(CAS-RN acid 2-yl}-methanone 1211586-75-2)

1.101 (1H-benzotriazol-5-yl)- 5-(2,2,2- 1H-benzo[d]- 487.4{(3aS,3bR,6aS,6bR)-5-[5-(2,2,2-trifluoro- trifluoroethoxy)-[1,2,3]triazole- (M + H)⁺ ethoxy)-pyridine-2-carbonyl]-octahydro-picolinic acid 5-carboxylic cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-(CAS-RN acid methanone 881409-53-6)

1.102 [(3aS,3bR,6aS,6bR)-5-(6- 6-(cyclopropyl- 1H-benzo[d]- 460.7cyclopropylmethoxy-pyridazine-3- methoxy)- [1,2,3]triazole- (M + H)⁺carbonyl)-octahydro-cyclobuta[1,2-c;3,4- pyridazine-3- 5-carboxylicc′]dipyrrol-2-yl]-(3,4-dimethyl-phenyl)- carboxylic acid acid methanone(CAS-RN

1184404-57-6) 1.103 (1H-benzotriazol-5-yl)- 5-bromo-2- 1H-benzo[d]-577.7 {(3aS,3bS,6aR,6bR)-5-[5-bromo-2-methyl- methyl-6-(2,2,2-[1,2,3]triazole- (M − H)⁻ 6-(2,2,2-trifluoro-ethoxy)-pyridine-3-trifluoroethoxy)- 5-carboxylic carbonyl]-octahydro-cyclobuta[1,2-c;3,4-nicotinic acid acid c′]dipyrrol-2-yl}-methanone

1.104 (1H-benzotriazol-5-yl)- 5-cyclopropyl-6- 1H-benzo[d]- 527.7{(3aS,3bS,6aR,6bR)-5-[5-cyclopropyl-6- (2,2,2- [1,2,3]triazole- (M + H)⁺(2,2,2-trifluoro-ethoxy)-pyridine-3- trifluoroethoxy)- 5-carboxyliccarbonyl]-octahydro-cyclobuta[1,2-c;3,4- nicotinic acid acidc′]dipyrrol-2-yl}-methanone (CAS-RN

1427064-90-1) 1.105 (1H-benzotriazol-5-yl)- 6-(2,2,2- 1H-benzo[d]- 555.6{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro- trifluoroethoxy)-[1,2,3]triazole- (M + H)⁺ ethoxy)-5-trifluoromethyl-pyridine-3-5-(trifluoro- 5-carboxylic carbonyl]-octahydro-cyclobuta[1,2-c;3,4-methyl)nicotinic acid c′]dipyrrol-2-yl}-methanone acid

1.106 (1H-benzotriazol-5-yl)- 5-(tetrahydro-2H- 1H-benzo[d]- 571.7{(3aS,3bS,6aR,6bR)-5-[5-(tetrahydro- pyran-4-yl)-6- [1,2,3]triazole-(M + H)⁺ pyran-4-yl)-6-(2,2,2-trifluoro-ethoxy)- (2,2,2-trifluoro-5-carboxylic pyridine-3-carbonyl]-octahydro- ethoxy)nicotinic acidcyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}- acid (CAS-RN methanone1427064-92-3)

1.107 (1H-benzotriazol-5-yl)- 4-(4- 1H-benzo[d]- 597.2{(3aS,3bR,6aS,6bR)-5-[4-(4-chloro- chlorophenyl)-5- [1,2,3]triazole-(M + H)⁺ phenyl)-5-(2,2,2-trifluoro-ethoxy)- (2,2,2-trifluoro-5-carboxylic pyridine-2-carbonyl]-octahydro- ethoxy)picolinic acidcyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}- acid (CAS-RN methanone1364677-00-8)

1.108 (1H-benzotriazol-5-yl)- 5-(furan-2-yl)-6- 1H-benzo[d]- 553.2{(3aS,3bS,6aR,6bR)-5-[5-furan-2-yl-6- (2,2,2-trifluoro- [1,2,3]triazole-(M + H)⁺ (2,2,2-trifluoro-ethoxy)-pyridine-3- ethoxy)nicotinic5-carboxylic carbonyl]-octahydro-cyclobuta[1,2-c;3,4- acid acidc′]dipyrrol-2-yl}-methanone

1.109 (1H-benzotriazol-5-yl)- 5-chloro-6-oxo-1- 1H-benzo[d]- 521.1{(3aS,3bS,6aR,6bR)-5-[5-chloro-6-(2,2,2- (2,2,2- [1,2,3]triazole- (M +H)⁺ trifluoro-ethoxy)-pyridine-3-carbonyl]- trifluoroethyl)-5-carboxylic octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol- 1,6-dihydro-acid 2-yl}-methanone pyridine-3-

carboxylic acid (intermediate 3) 1.110 [(3aS,3bR,6aS,6bR)-5-(4-ethoxy-4- 4-fluoro-1H- 501.2 quinoline-2-carbonyl)-octahydro- ethoxyquinoline-benzo[d]- (M + H)⁺ cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-2-carboxylic acid [1,2,3]triazole-fluoro-1H-benzotriazol-5-yl)-methanone (CAS-RN 40609- 5-carboxylic

78-7) acid (intermediate 10) 1.111 {(3aS,3bS,6aR,6bR)-5-[5- 5-1H-benzo[d]- 565.2 methanesulfonyl-6-(2,2,2-trifluoro- (methylsulfonyl)-[1,2,3]triazole- (M + H)⁺ ethoxy)-pyridine-3-carbonyl]-octahydro-6-(2,2,2-trifluoro- 5-carboxylic cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-ethoxy)nicotinic acid phenyl-methanone acid (intermediate

5)

Example 2(3aR,3bS,6aR,6bS)-5-(1H-Benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester

To a solution of(3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole(intermediate 1; 40 mg, 289 mol) in N,N-dimethylformamide (2 mL) wereadded N-methylmorpholine (146 mg, 1.45 mmol),1H-benzo[d][1,2,3]triazole-5-carboxylic acid (47.2 mg, 289 μmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (110 mg, 289 mol). In the meantime a secondsolution with (4-(trifluoromethoxy)phenyl)methanol (CAS-RN 1736-74-9;55.6 mg, 289 μmol) and 1,1′-carbonyldiimidazole (49.3 mg, 304 μmol) inDMF (2 ml) was prepared. The two reaction mixtures were stirred at roomtemperature for 4 h, then combined and stirred for another 16 h, thenpartitioned between sat. aq. ammonium chloride solution and ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, filtered and evaporated. Chromatography (silica gel; gradientdichloromethane to dichloromethane/methanol/25% aq. ammonia solution90:10:0.25) produced the title compound (38 mg, 26%). White solid, MS:502.3 (M+H)⁺.

Example 2.001(3aR,3bS,6aR,6bS)-5-(1H-Benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylicacid 3,5-dichloro-benzyl ester

The title compound was produced in analogy to example 2, replacing(4-(trifluoromethoxy)-phenyl)methanol by (3,5-dichlorophenyl)methanol(CAS-RN 60211-57-6). White solid, MS: 486.5 (M+H)⁺.

Example 3(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4′-fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone

(3aS,3bR,6aS,6bR)-5-(4′-Fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylicacid tert-butyl ester (intermediate 12; 26 mg, 55.0 μmol) was combinedwith hydrochloric acid solution (5-6 M in 2-propanol; 1 mL) and stirredat room temperature for 18 h. After evaporation of volatile material theresidue was taken up in N,N-dimethylformamide (1 mL), thenN-methylmorpholine (27.8 mg, 275 mol),1H-benzo[d][1,2,3]triazole-5-carboxylic acid (9.9 mg, 61 mol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (23 mg, 61 mol) were added. After 16 h the reactionmixture was partitioned between water sat. aq. ammonium chloridesolution and ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, filtered, and evaporated. Chromatography(silica gel; gradient dichloromethane to dichloromethane/methanol/25%aq. ammonia solution 90:10:0.25) produced the title compound (26 mg,82%). Light yellow gum, MS: 516.6 (M−H)⁻.

Example 3.001(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-chloro-naphthalene-2-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone

A solution of 6-chloro-naphthalene-2-sulfonyl chloride (CAS-RN102153-63-9, 33.6 mg, 129 μmol) in dichloromethane (1 mL) was added atroom temperature to a solution of(3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole(intermediate 1; 11.9 mg, 86 μmol) in dichloromethane (2 mL) andpyridine (33.9 mg, 34.7 μl, 428 μmol, Eq: 5), then after 4 h thereaction mixture was evaporated. The residue was taken up withN,N-dimethylformamide, then 1H-benzo[d]-[1,2,3]triazole-5-carboxylicacid (14.0 mg, 86 μmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (35.8 mg, 94 μmol) and 4-methylmorpholine (43.3 mg,428 μmol) were added, then after 16 h the reaction mixture waspartitioned between sat. aq. ammonium chloride solution and ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, filtered, and evaporated. Chromatography (silica gel;dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) producedthe title compound (4 mg, 9%). Colourless gum, MS: 508.6 (M+H)⁺.

Example 4[(3aR,3bS,6aR,6bS)-5-(1H-Benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone

To a solution of(3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole(intermediate 1; 30 mg, 217 μmol) and N-methylmorpholine (108 mg, 1.07mmol) and N,N-dimethylformamide (3 mL) was added a solution of6-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carbonyl chloride(intermediate 7; 57 mg, 214 mol) in N,N-dimethylformamide DMF (1 ml)dropwise at room temperature, then after 1 h1H-benzo[d][1,2,3]triazole-5-carboxylic acid (34.9 mg, 214 mol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (81.4 mg, 214 mol) were added. After another 16 hthe reaction mixture was partitioned between sat. aq. ammonium chloridesolution and ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, filtered, and evaporated. Chromatography(silica gel; dichloromethane/methanol/25% aq. ammonia solution90:10:0.25) produced the title compound (24 mg, 22%). White solid, MS:511.4 (M+H)⁺.

INTERMEDIATES Intermediate 1(3aS,3bS,6aR,6bR)-Decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole Step 1:(3aS,3bS,6aR,6bR)-2,5-Dibenzyl-tetrahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-1,3,4,6-tetraone

A solution of 1-benzyl-1H-pyrrole-2,5-dione (1.12 g, 5.98 mmol) inacetonitrile (60 ml) was purged with nitrogen for 10 min, thenirradiated at 300 nm for 6 h to produce a white suspension. About 30 mLof acetonitrile was distilled off, then the product was collected byfiltration (447 mg, 40%). Off-white solid, MS: 375.5 (M+H)⁺, ¹H-NMR (300MHz, DMSO-d₆): 7.35-7.25 (m, 10H), 4.63 (s, 4H), 3.45 (s, 4H).

Step 2:(3aS,3bS,6aR,6bR)-2,5-Dibenzyl-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole

To a suspension of lithium aluminum hydride (3.05 g, 80.3 mmol) indiethyl ether (120 mL) was added portionwise(3aS,3bS,6aR,6bR)-2,5-dibenzyl-tetrahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-1,3,4,6-tetraone(7.52 g, 20.1 mmol) over 10 min at room temperature. The reactionmixture was stirred at room temperature for 4 h, then cooled down to 0°C. and quenched by slow addition of water (40 mL) and 2 M aq. sodiumhydroxide solution. Water (500 mL) and ethyl acetate (500 mL) wereadded, then after filtration through diatomaceous earth the organiclayer was washed with brine, dried over magnesium sulfate, filtered, andevaporated. The residue was triturated in methanol (40 mL) to producethe title compound (4.60 g, 72%). White solid, MS: 319.6 (M+H)⁺, ¹H-NMR(300 MHz, CDCl₃): 7.4-7.2 (m, 10H), 3.65 (s, 4H), 2.82 (d, J=9.3, 4 H),2.39 (d, J=4.4, 4 H), 2.05 (dd, J=9.3, 4.4, 4 H).

Step 3: (3aS,3bS,6aR,6bR)-Decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole

A solution of(3aS,3bS,6aR,6bR)-2,5-dibenzyl-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole(4.6 g, 14.4 mmol, Eq: 1.00) was stirred for 4 h at 50° C. under ahydrogen atmosphere (3 bar) in the presence of palladium (10% onactivated charcoal, 2.08 g), then insoluble material was removed byfiltration through diatomaceous earth. The filtrate was evaporated toproduce the title compound (1.72 g, 86%). White solid, MS: 139.2 (M+H)⁺,¹H-NMR (300 MHz, CDCl₃): 2.99 (d, J=11.4, 4 H), 2.68 (dd, J=11.4, 4.4, 4H), 2.25-2.15 (m, 6H).

Intermediate 2 4-isopropoxy-7-(trifluoromethyl)quinoline-2-carboxylicacid Step 1: Methyl4-isopropoxy-7-(trifluoromethyl)quinoline-2-carboxylate

To a stirring suspension of methyl4-hydroxy-7-(trifluoromethyl)quinoline-2-carboxylate (300 mg, 1.08 mmol)in acetonitrile (3 mL) were added potassium carbonate (449 mg, 3.25mmol) and 2-iodopropane (570 mg, 3.25 mmol). The reaction mixture wasstirred for 16 h at 80° C., then partitioned between water and ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, filtered, and evaporated. Chromatography (silica gel;heptane-ethyl acetate gradient) produced the title compound (334 mg,98%) as a white solid.

Step 2: 4-Isopropoxy-7-(trifluoromethyl)quinoline-2-carboxylic acid

A mixture of methyl4-isopropoxy-7-(trifluoromethyl)quinoline-2-carboxylate (330 mg, 1.05mmol), potassium hydroxide (209 mg, 3.16 mmol), ethanol (3.5 mL), andwater (3.5 mL) was heated at 80° C. for 45 min, then most of the ethanolwas distilled off. The remaining aqueous solution was acidified to pH 1with 1 M hydrochloric acid solution. The precipitate was collected byfiltration and dried to produce the title compound (304 mg, 96%). Whitesolid MS: 299.9 (M+H)⁺.

The following intermediates were produced in analogy to intermediate 2,replacing methyl 4-hydroxy-7-(trifluoromethyl)quinoline-2-carboxylateand 2-iodopropane by the appropriate starting material and alkylatingagent, respectively.

No. Systematic name Starting material alkylating agent MS, m/e 2.11-ethyl-4-(2,2,2- methyl 1-ethyl-4-hydroxy- 2,2,2- 288.4trifluoroethoxy)-1H- 1H-indole-6-carboxylate trifluoroethylindole-6-carboxylic acid (CAS-RN 934617-51-3) trifluoromethane-sulfonate 2.2 4-ethoxy-6- methyl 4-hydroxy-6- iodoethane 286.5(trifluoromethyl)quinoline- (trifluoromethyl)quinoline-2- 2-carboxylicacid carboxylate (CAS-RN 1422284-64-7) 2.3 4-(2-methoxyethoxy)-7- methyl4-hydroxy-7- 1-bromo-2- 316.5 (trifluoromethyl)quinoline-(trifluoromethyl)quinoline-2- methoxyethane (M + H)⁺ 2-carboxylic acidcarboxylate (CAS-RN 1072944-69-4) 2.4 4-isopropoxy-5,6,7,8- methyl4-hydroxy-5,6,7,8- 2-iodopropane 233.3 tetrahydronaphthalene-2-tetrahydronaphthalene-2- (M − H)⁻ carboxylic acid carboxylate (CAS-RN184107-09-3) 2.5 7-chloro-4- methyl 7-chloro-4- iodoethane 252.5ethoxyquinoline-2- hydroxyquinoline-2- (M + H)⁺ carboxylic acidcarboxylate 2.6 1-ethyl-4-propan-2- methyl 1-ethyl-4-hydroxy-2-iodopropane 248.6 yloxyindole-6-carboxylic 1H-indole-6-carboxylate(M + H)⁺ acid (CAS-RN 934617-51-3) 2.8 4-ethoxy-7- methyl 4-hydroxy-7-iodoethane 248.2 methoxyquinoline-2- methoxyquinoline-2- (M + H)⁺carboxylic acid carboxylate (CAS-RN 259214-73-8) 2.9 4-ethoxy-1-(2,2,2-methyl 4-ethoxy-1H-indole- 2,2,2-trifluoro- 288.5trifluoroethyl)-1H-indole- 6-carboxylate (CAS-RN ethyl trifluoro- (M +H)⁺ 6-carboxylic acid 372099-86-0) methanesulfonate

Intermediate 3

5-Chloro-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxylicacid

Lithium hydroxide monohydrate (102 mg, 2.4 mmol) was added to a solutionof methyl5-chloro-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxylate(328 mg, 1.22 mmol) in tetrahydrofuran (1 mL) and water (1 mL), thenafter 16 h the reaction mixture was partially evaporated in order toremove most of the tetrahydrofuran. The remaining aqueous solution wasacidified to pH 1 with 1 M aq. hydrochloric acid solution. Theprecipitate was collected by filtration and dried to afford the titlecompound (289 mg, 93%). White solid, MS: 254.2 (M−H)⁻.

The following intermediates were prepared in analogy to intermediate 3,replacing methyl5-chloro-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxylateby the appropriate starting material.

No. Systematic name Starting material MS, m/e 3.14-ethoxy-1-ethyl-1H-indole-6- methyl 4-ethoxy-1-ethyl-1H-indole- 234.5carboxylic acid 6-carboxylate (CAS-RN 372099-98- (M + H)⁺ 4) 3.25-(4-chlorophenyl)-6-oxo-1,6- methyl 5-(4-chlorophenyl)-6- 248.1dihydropyridine-2-carboxylic acid hydroxypicolinate (M − H)⁻ 3.34-isopropoxy-1H-indole-6-carboxylic methyl 4-isopropoxy-1H-indole-6-218.3 acid carboxylate (intermediate 9, step 1) (M − H)⁻

Intermediate 4 5-Cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid

5-Cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinonitrile (250 mg, 1.03mmol) was combined with 25% aq. hydrochloric acid solution (5 mL) andheated at 110° C. for 3 h. After cooling the reaction mixture wasevaporated to dryness. The residue was suspended in water (5 mL)basified with 6 M aq. sodium hydroxide solution, then the resultingsolution was acidified to pH 1. The precipitate was collected byfiltration and dried to produce the title compound (159 mg, 59%). Whitesolid, MS: 262.2 (M+H)+.

Intermediate 5 5-(Methylsulfonyl)-6-(2,2,2-trifluoroethoxy)nicotinicacid Step 1: Methyl5-(methylsulfonyl)-6-(2,2,2-trifluoroethoxy)nicotinate

A mixture of L-proline (88 mg, 0.76 mmol, Eq: 0.8) and sodium hydroxide(31 mg, 0.76 mmol) and dimethyl sulfoxide (5 mL), was stirred at roomtemperature for 30 min, then methyl5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate (300 mg, 955 mol), sodiummethanesulfinate (804 mg, 7.64 mmol) and copper(I) iodide (146 mg, 764mol) were added, and the reaction mixture was heated at 80° C. for 16 h,then partitioned between 1 M aq. hydrochloric acid solution and ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, filtered, and evaporated. The residue was purified bychromatography (silica gel; heptane-ethyl acetate gradient produced thetitle compound (80 mg, 27%). White solid, MS: 314 (M+H)⁺.

Step 2: 5-(Methylsulfonyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid

The title compound was produced in analogy to intermediate 2, step 2from methyl 5-(methyl sulfonyl)-6-(2,2,2-trifluoroethoxy)nicotinate.White solid, MS: 298.1 (M−H)⁻.

Intermediate 61-(3-Methoxy-propyl)-1,2,3,4-tetrahydro-quinoline-3-carboxylic acid

A mixture of methyl 1,2,3,4-tetrahydroquinoline-3-carboxylate (CAS-RN177202-62-9; 300 mg, 1.57 mmol) 1-bromo-3-methoxypropane (735 mg, 4.71mmol) and sodium hydrogencarbonate (659 mg, 7.84 mmol) in ethanol (3 mL)was heated at reflux. After 18 h the reaction mixture was evaporated andthe residue chromatographed (silica gel; heptane-ethyl acetate gradient)to produce a mixture of1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinoline-3-carboxylic acidmethyl ester and1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinoline-3-carboxylic acidethyl ester (251 mg). This material was combined with ethanol (2.5 mL),water (2.5 mL) and potassium hydroxide (264 mg, 4.71 mmol) and heated at80° C. for 45 min, then the reaction mixture was partially evaporated inorder to remove most of the ethanol. The remaining aqueous solution waspartitioned between ethyl acetate and 1 M aq. hydrochloric acidsolution. The organic layer was washed with brine, dried over magnesiumsulfate, filtered, and evaporated to produce the title compound (190 mg,49%). Light yellow oil, MS: 248.5 (M−H)⁻.

Intermediate 76-(Trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carbonyl chloride

To a white suspension of6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (CAS-RN215798-14-4; 500 mg, 2.04 mmol) and pyridine (339 mg, 4.29 mmol) indichloromethane (5 mL) was added dropwise a solution of triphosgene (273mg, 918 mol) in dichloromethane (5 mL) at 0° C. After 30 min the icebath was removed, then after 16 h the reaction mixture was partitionedbetween 1 M aq. hydrochloric acid solution and dichloromethane. Theorganic layer was washed with brined, dried over magnesium sulfate,filtered, and evaporated to produce the title compound (546 mg, quant.)as a yellow oil.

Intermediate 8 4-Ethoxy-5,6,7,8-tetrahydroquinoline-2-carboxylic acidStep 1: Methyl 4-hydroxy-5,6,7, 8-tetrahydroquinoline-2-carboxylate

A solution of methyl 4-hydroxyquinoline-2-carboxylate (CAS-RN 5965-59-3;1.0 g, 4.92 mmol) in 37% aq. hydrochloric acid solution (36 mL) wasstirred at room temperature under an atmosphere of hydrogen (4 bar) inthe presence of platinum(IV) oxide (124 mg). After 72 h insolublematerial was removed by filtration through diatomaceous earth, and thefiltrate was evaporated to produce the title compound (1.06 g, 69%).White solid, MS: 208.3 (M+H)⁺.

Step 2: Methyl 4-ethoxy-5,6,7, 8-tetrahydroquinoline-2-carboxylate

The title compound was produced in analogy to intermediate 2, step 1from methyl 4-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxylate. Whitesolid, MS: 236.3 (M+H)⁺.

Step 3: 4-Ethoxy-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

A mixture of methyl 4-ethoxy-5,6,7,8-tetrahydroquinoline-2-carboxylate(156 mg, 663 mol, Eq: 1.00) in ethanol (2 mL) and water (2 mL) washeated at reflux for 2 h, then most of the ethanol was distilled off andthe remaining aqueous solution was acidified to pH 1, then evaporated todryness. The residue was suspended in dichloromethane, then insolublematerial was removed by filtration. The filtrate was evaporated toproduce the title compound (172 mg, quant.). White solid, MS: 222.3(M+H)⁺.

Intermediate 9 4-Isopropoxy-1-methyl-1H-indole-6-carboxylic acid Step 1:Methyl 4-isopropoxy-1H-indole-6-carboxylate

Potassium carbonate (651 mg, 4.71 mmol) and 2-iodopropane (275 mg, 1.57mmol) were added to a solution of methyl4-hydroxy-1H-indole-6-carboxylate (CAS-RN 77140-48-8; 300 mg, 1.57 mmol)in N,N-dimethylformamide (9 mL) at 0° C. The reaction mixture wasstirred for 16 h at 0° C., then partitioned between water and ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, filtered and evaporated to give a light brown oil.

Chromatography (silica gel; heptane-ethyl acetate gradient) produced thetitle compound (280 mg, 77%). White solid, MS: 232.2 (M−H)⁻.

Step 2: Methyl 4-isopropoxy-1-methyl-1H-indole-6-carboxylate

Potassium carbonate (296 mg, 2.14 mmol) and iodomethane (183 mg, 1.29mmol) were added to a solution of methyl4-isopropoxy-1H-indole-6-carboxylate (100 mg, 429 mol) in acetone (2.5mL). The reaction mixture was heated at reflux for 16 h, thenpartitioned between water and ethyl acetate. The organic layer waswashed with brine, dried over magnesium sulfate, filtered and evaporatedto give a light brown oil. Chromatography (silica gel; heptane-ethylacetate gradient) produced the title compound (102 mg, 96%). Colourlessoil, MS: 248.2 (M−H)⁻.

Step 3: 4-Isopropoxy-1-methyl-1H-indole-6-carboxylic acid

The title compound was produced in analogy to intermediate 2, step 2from methyl 4-isopropoxy-1-methyl-1H-indole-6-carboxylate. Off-whitesolid, MS: 232.2 (M−H)⁻.

Intermediate 10 4-Fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylic acidStep 1: 5-Bromo-4-fluoro-1H-benzo[d][1,2,3]triazole

To a light brown suspension of 4-bromo-3-fluorobenzene-1,2-diamine (1.50g, 7.32 mmol) in water (15 mL) and acetic acid (5 mL) was added asolution of sodium nitrite (555 mg, 8.05 mmol) in water (1.5 mL)dropwise at 0° C. After 1 h at 0° C. the reaction mixture was heated to85° C. for 1 h. After cooling the reaction mixture was partitionedbetween water and ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate, filtered and evaporated to producethe title compound (1.53 g, 97%). Brown solid, MS: 214.1 (M−H)⁻.

Step 2: Methyl 4-fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylate

A solution of 5-bromo-4-fluoro-1H-benzo[d][1,2,3]triazole (415 mg, 1.92mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (63.4 mg, 76.8 mol), and triethylamine (253 mg,2.50 mmol) in methanol (5 mL) was stirred for 18 h under a hydrogenatmosphere (70 bar) at 110° C. After cooling the reaction mixture wasevaporated and the residue was purified by chromatography (silica gel;gradient dichloromethane to dichloromethane/methanol 95:5) to producethe title compound (127 mg, 31%). Red solid, MS: 194.2 (M−H)⁻.

Step 3: 4-Fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid

The title compound was produced in analogy to intermediate 3 from methyl4-fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylate. Brown solid, MS:180.2 (M−H)⁻.

Intermediate 11(+)-(R)-4,5,6,7-Tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid

Racemic 4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid(CAS-RN 33062-47-4; 1.10 g, 6.58 mmol) was separated by preparative HPLCusing a Chiralpak AD column as the stationary phase and heptane/ethanol3:2 as the mobile phase. This produced the faster eluting(+)-(R)-enantiomer (452 mg, 41%), followed by the slower eluting(−)-(S)-enantiomer (381 mg, 35%). White solid, MS: 166.2 (M−H)⁻.

Intermediate 12(3aS,3bR,6aS,6bR)-5-(4′-Fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylicacid tert-butyl ester

A solution of 4′-fluorobiphenyl-4-sulfonyl chloride (CAS-RN 116748-66-4;42.9 mg, 158 mol) in dichloromethane (1 mL) was added at roomtemperature to a solution of(3aR,3bS,6aR,6bS)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylicacid tert-butyl ester hydrochloride (intermediate 13; 29 mg, 106 mol)and pyridine (25.0 mg, 317 mol) in dichloromethane (1 mL). After 2 h thereaction mixture was concentrated under vacuum, and the residue waspurified by chromatography (silica gel; heptane-ethyl acetate gradient)to produce the title compound (30 mg, 60%). White solid, MS: 394.6(M+Me₃COCO+Na)⁺.

Intermediate 13(3aR,3bS,6aR,6bS)-Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylicacid tert-butyl ester hydrochloride Step 1:(3aS,3bS,6aR,6bR)-Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2,5-dicarboxylicacid di-tert-butyl ester

To a solution of(3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole(intermediate 1; 100 mg, 724 mol) in chloroform (3 ml) was addeddropwise a solution of di-tert-butyl dicarbonate (474 mg, 2.17 mmol) inchloroform (3 ml). After 2 h the reaction mixture was evaporated and theresidue was chromatographed (silica gel; heptane-ethyl acetate gradient)to produce the title compound (222 mg, 91%). White solid, MS: 338.6(M+H)⁺.

Step 2:(3aR,3bS,6aR,6bS)-Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylicacid tert-butyl ester hydrochloride

Hydrogen chloride solution (5-6 M in 2-propanol, 90 μL, 0.45 mmol) wasadded at 0° C. to a solution of(3aS,3bS,6aR,6bR)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2,5-dicarboxylicacid di-tert-butyl ester (76 mg, 225 mol) in ethyl acetate (2 mL). Thereaction mixture was stirred at room temperature for 3 days, then theprecipitate was collected by filtration and dried to afford the titlecompound (33 mg, 48%). White solid, MS: 239.6 (M+H)⁺.

Example A

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of tablets of the followingcomposition:

Per tablet Active ingredient 200 mg  Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg 

Example B

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of capsules of the followingcomposition:

Per capsule Active ingredient 100.0 mg Corn starch  20.0 mg Lactose 95.0 mg Talc  4.5 mg Magnesium stearate  0.5 mg 220.0 mg

1. A compound of formula (I)

wherein R¹ is substituted quinolinyl, substituted1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl, substituted1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazolyl, substitutedchromanyl, substituted indolyl, substituted naphthyl, substitutedoxazolyl, substituted phenyl, substituted phenylalkyl, substitutedphenylcycloalkyl, substituted phenoxyalkyl, substituted phenylalkoxy,substituted phenylalkenyl, substituted phenylalkynyl, substitutedpyridazinyl, substituted pyridazinylalkyl, substitutedpyridazinylalkenyl, substituted pyridazinylalkynyl, substitutedpyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl,substituted pyridinylalkynyl, substituted pyridinonyl, substitutedpyridinonylalkyl, substituted pyridinonylalkenyl, substitutedpyridinonylalkynyl, substituted thiophenyl, substituted thiophenylalkyl,substituted thiophenylalkenyl, substituted thiophenylalkynyl,substituted tetralinyl or substituted tetralinonyl, wherein substitutedquinolinyl, substituted 1,2,3,4-tetrahydroquinolinyl, substitutedisoquinolinyl, substituted 1,2,3,4-tetrahydroisoquinolinyl, substituted9H-carbazolyl, substituted chromanyl, substituted indolyl, substitutednaphthyl, substituted oxazolyl, substituted phenyl, substitutedphenylalkyl, substituted phenylcycloalkyl, substituted phenoxyalkyl,substituted phenylalkoxy, substituted phenylalkenyl, substitutedphenylalkynyl, substituted pyridazinyl, substituted pyridazinylalkyl,substituted pyridazinylalkenyl, substituted pyridazinylalkynyl,substituted pyridinyl, substituted pyridinylalkyl, substitutedpyridinylalkenyl, substituted pyridinylalkynyl, substituted pyridinonyl,substituted pyridinonylalkyl, substituted pyridinonylalkenyl,substituted pyridinonylalkynyl, substituted thiophenyl, substitutedthiophenylalkyl, substituted thiophenylalkenyl, substitutedthiophenylalkynyl, substituted tetralinyl and substituted tetralinonylare substituted with R⁶, R⁷ and R⁸; Y is —C(O)— or —S(O)₂—; R² issubstituted pyridinyl, substituted phenyl or is selected from the ringsystems A, B and C, wherein substituted pyridinyl and substituted phenylare substituted with one substituted aminosulfonyl, wherein substitutedaminosulfonyl is substituted on the nitrogen atom with one to twosubstituents independently selected from H, alkyl, cycloalkyl,cycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;

R³, R⁴ and R⁵ are independently selected from H, alkyl, halogen,haloalkyl and alkoxy; R⁶, R⁷ and R⁸ are independently selected from H,halogen, cyano, cyanoalkyl, alkyl, hydroxyalkyl, haloalkyl,hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy,cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy,alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy,alkoxyalkoxyalkyl, alkylsulfonyl, furanyl, tetrahydropyranyl, phenyl,substituted phenyl, phenylalkoxy, substituted phenylalkoxy, pyridinyl,substituted pyridinyl, pyrrolyl, substituted pyrrolyl, pyrrolydinyl andsubstituted pyrrolydinyl, wherein substituted phenyl, substitutedphenylalkoxy, substituted pyridinyl, substituted pyrrolyl andsubstituted pyrrolydinyl are substituted with one to three halogen; orpharmaceutically acceptable salts.
 2. The compound according to claim 1,wherein R¹ is substituted quinolinyl, substituted1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl, substituted1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazolyl, substitutedchromanyl, substituted indolyl, substituted naphthyl, substitutedoxazolyl, substituted phenyl, substituted phenylalkyl, substitutedphenoxyalkyl, substituted phenylalkoxy, substituted phenylalkenyl,substituted pyridazinyl, substituted pyridinyl, substituted pyridinonyl,substituted tetralinyl or substituted tetralinonyl, wherein substitutedquinolinyl, substituted 1,2,3,4-tetrahydroquinolinyl, substitutedisoquinolinyl, substituted 1,2,3,4-tetrahydroisoquinolinyl, substituted9H-carbazolyl, substituted chromanyl, substituted indolyl, substitutednaphthyl, substituted oxazolyl, substituted phenyl, substitutedphenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy,substituted phenylalkenyl, substituted pyridazinyl, substitutedpyridinyl, substituted pyridinonyl, substituted tetralinyl andsubstituted tetralinonyl are substituted with R⁶, R⁷ and R⁸.
 3. The Acompound of claim 1, wherein R¹ is substituted quinolinyl, substitutedindolyl, substituted naphthyl, substituted phenylalkoxy, substitutedphenylalkenyl or substituted pyridinyl, wherein substituted quinolinyl,substituted indolyl, substituted naphthyl, substituted phenylalkoxy,substituted phenylalkenyl and substituted pyridinyl are substituted withR⁶, R⁷ and R⁸.
 4. The A compound of claim 1, wherein R¹ is substitutedquinolinyl, substituted indolyl, substituted naphthyl or substitutedpyridinyl, wherein substituted quinolinyl, substituted indolyl,substituted naphthyl and substituted pyridinyl are substituted with R⁶,R⁷ and R⁸.
 5. The A compound of claim 1, wherein R² is selected from thering systems A and C.
 6. The A compound of claim 1, wherein R² is thering system A.
 7. The A compound of claim 1, wherein Y is —C(O)—.
 8. TheA compound of claim 1, wherein R³, R⁴ and R⁵ are independently selectedfrom H and halogen.
 9. The A compound of claim 1, wherein R³, R⁴ and R⁵are H.
 10. The A compound of claim 1, wherein R⁶ is H, halogen, cyano,cyanoalkyl, alkyl, haloalkyl, cycloalkylalkoxy, alkoxy, alkoxyalkyl,haloalkoxy, alkoxyalkoxy, phenyl, phenylalkoxy or phenyl substitutedwith one to three halogen.
 11. The A compound of claim 1, wherein R⁶ isalkoxy, haloalkoxy or alkoxyalkoxy.
 12. The A compound of claim 1,wherein R⁷ is H, halogen, alkyl, cycloalkyl, alkoxy, haloalkoxy,alkylsulfonyl, furanyl or tetrahydropyranyl.
 13. The A compound of claim1, wherein R⁷ is H or halogen.
 14. The A compound of claim 1, wherein R⁸is H or alkyl.
 15. The A compound of claim 1, wherein R⁸ is H.
 16. The Acompound of claim 1, selected from[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-naphthalen-2-yl)-methanone;1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propan-1-one;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4′-fluoro-biphenyl-4-yl)-methanone;(E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-bromo-naphthalen-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-methoxy-naphthalen-2-yl)-methanone;(E)-1-[(3aS,3bS,6aR,6bR)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone;6-[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-naphthalene-2-carbonitrile;1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-2-(4-trifluoromethoxy-phenoxy)-ethanone;1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-2-(2-isopropyl-phenoxy)-ethanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(5-trifluoromethoxy-1H-indol-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-trifluoromethoxy-1H-indol-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-naphthalen-2-yl-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-methyl-naphthalen-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(7-methyl-naphthalen-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-phenyl-naphthalen-2-yl)-methanone;(6-bromo-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4′-chloro-biphenyl-4-yl)-methanone;(4′-chloro-biphenyl-4-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(5-trifluoromethoxy-1H-indol-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-trifluoromethoxy-1H-indol-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(3-methoxy-naphthalen-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-methoxy-naphthalen-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-indol-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-methyl-1H-indol-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-cyclopropylmethoxy-naphthalen-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-methoxy-naphthalen-2-yl)-methanone;2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-1H-indole-5-carbonitrile;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(3-methoxy-phenyl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-methoxy-quinolin-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-methanone;[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1,2,3,4-tetrahydro-naphthalen-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-methyl-5-trifluoromethoxy-1H-indol-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-1H-indol-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-1-methyl-1H-indol-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-methyl-1H-indol-2-yl)-methanone;{2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-indol-1-yl}-acetonitrile;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-isobutyl-1H-indol-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-quinolin-2-yl-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-isoquinolin-3-yl-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-indol-6-yl)-methanone;3-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-3,4-dihydro-2H-naphthalen-1-one;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-chroman-2-yl-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-indol-5-yl)-methanone;(4-methoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[6-(4-chloro-phenyl)-pyridin-3-yl]-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-methoxy-isoquinolin-3-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-methyl-quinolin-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(5-chloro-1H-indol-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-naphthalen-2-yl]-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(7-phenyl-naphthalen-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-ethoxy-naphthalen-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-naphthalen-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-benzyloxy-1H-indol-6-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone;[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-methanone;[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[1-(2-methoxy-ethoxy)-isoquinolin-3-yl]-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-cyclopropylmethoxy-isoquinolin-3-yl)-methanone;(4-isopropoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[1-(2,2,2-trifluoro-ethoxy)-isoquinolin-3-yl]-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-1H-indol-6-yl)-methanone;4-[(3aS,3bS,6aR,6bR)-5-(4-isopropoxy-naphthalene-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-benzenesulfonamide;[6-(4-chloro-phenyl)-pyridin-3-yl]-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;(1-cyclopropylmethoxy-isoquinolin-3-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-1-methyl-1H-indol-6-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-ethoxy-quinolin-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-quinolin-2-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-9H-carbazol-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-quinolin-2-yl]-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-7-trifluoromethyl-quinolin-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-cyclopropylmethoxy-quinolin-2-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[5-(4-chloro-phenyl)-pyridin-2-yl]-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-ethoxy-isoquinolin-3-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-ethyl-4-isopropoxy-1H-indol-6-yl)-methanone;6-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-3-(4-chloro-phenyl)-1H-pyridin-2-one;1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(7-chloro-4-ethoxy-quinolin-2-yl)-methanone;(7-chloro-4-ethoxy-quinolin-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(2-methoxy-ethoxy)-7-trifluoromethyl-quinoline-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;(1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-6-trifluoromethyl-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-ethoxy-1-ethyl-1H-indol-5-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[1-ethyl-4-(2,2,2-trifluoro-ethoxy)-1H-indol-5-yl]-methanone;5-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-pyridine-2-sulfonicacid amide;(1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(2,2,2-trifluoro-ethoxy)-quinoline-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;(1H-benzotriazol-5-yl)-(3aS,3bS,6aR,6bR)-5-[4-ethoxy-1-(2,2,2-trifluoro-ethyl)-1H-indole-6-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;(1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-chloro-4-cyclopropylmethoxy-pyridine-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;(1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;(3,4-dimethyl-phenyl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-5,6,7,8-tetrahydro-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;(1H-benzotriazol-5-yl)-[(3aS,3bS,6aR,6bR)-5-(4′-chloro-biphenyl-3-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;(1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-7-methoxy-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;[(3aS,3bS,6aR,6bR)-5-(4-Ethoxy-6-trifluoromethyl-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-methanone;[(3aS,3bS,6aR,6bR)-5-(1-ethoxy-isoquinoline-3-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-methanone;(1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[5-cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-cyclopropyl-5-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone′]dipyrrol-2-yl}-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-4-ethoxy-quinolin-2-yl)-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;(1H-benzotriazol-5-yl)-(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl})-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl})-methanone;[(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-pyridazine-3-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(3,4-dimethyl-phenyl)-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-2-methyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-5-trifluoromethyl-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-(tetrahydro-pyran-4-yl)-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl)}-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-furan-2-yl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl})-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-chloro-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-fluoro-1H-benzotriazol-5-yl)-methanone;{(3aS,3bS,6aR,6bR)-5-[5-methanesulfonyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-phenyl-methanone;(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylicacid4-trifluoromethoxy-benzyl ester;(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylicacid 3,5-dichloro-benzyl ester;(1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4′-fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;(1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-chloro-naphthalene-2-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone;and pharmaceutically acceptable salts thereof.
 17. The A compound ofclaim 16, selected from(E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone;(4-isopropoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;4-[(3aS,3bS,6aR,6bR)-5-(4-isopropoxy-naphthalene-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-benzenesulfonamide;[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-1-methyl-1H-indol-6-yl)-methanone;[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-quinolin-2-yl]-methanone;(1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl})-methanone;(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylicacid4-trifluoromethoxy-benzyl ester; and pharmaceutically acceptable saltsthereof.
 18. A process to prepare a compound of claim 1 comprising thereaction of a compound of formula (II) in the presence of a compound offormula (III), wherein R¹, R², A and Y are as defined above.


19. (canceled)
 20. A pharmaceutical composition comprising a compound ofclaim 1 and a therapeutically inert carrier. 21-23. (canceled)
 24. Amethod for the treatment or prophylaxis a condition selected from thegroup consisting of renal conditions, liver conditions, inflammatoryconditions, conditions of the nervous system, conditions of therespiratory system, vascular and cardiovascular conditions, fibroticdiseases, cancer, ocular conditions, metabolic conditions, cholestaticand other forms of chronic pruritus and acute and chronic organtransplant rejection, which method comprises administering an effectiveamount of a compound of claim
 1. 25-26. (canceled)